Guofan Xiong
email: guofanx@gmail.com-maledop@gmail.com

Daniel Plata

Chu-Yin Chen

Huge Balls: An exploration of the comprehension of ludonarrative elements of a game art installation

Keywords: Interactive Art, Games, Interactivity, Game Art, Ludo-narrative, Gameplay, Visual Vocabularies

)

The strategies

Method

In this installation, we use the rules-based video game system as artistic materials to create an installation that provides a strange ludic experience yet with a faç ade of familiarity. Furthermore, we are hoping to deconstruct its conventional form to question our understanding of the video game medium, taking into account Upton's remarks about the importance of the players' background:

The game design is structuring a total experience (both rules and fantasy) that will coax the player toward adopting an interesting set of internal constraints, and what the internal constraints a player adopts will depend heavily on his conceptual background. The rules here are the game's inner framework of the restrictions and affordances, and the fantasy is the pleasing "wrapper." [START_REF] Upton | The Aesthetic of Play[END_REF] For achieving this experimentation, we decide to reverse the inducing and to isolate the rules/play (the juggling) and the fantasy (the visuals and the interfaces) to make it difficult for the players to adopt concrete internal constraints. Thus they cannot depend on their conceptual background to give sense to the play and further question their understanding of the installation.

The installation gives a little control over the balancing game, but completely free on how to play and what is the game. It constantly demands its players to adapt and remaining open on to the concept of play. The idea is to de-familiarize and estrange us from reality so that the players struggle to resituate themselves within it. The more they believe that language, stories, and narrative patterns determine the perception of reality (instead of believing that they determined by reality), the more this strategy works. [START_REF] Schrank | Avant-Garde Videogames: Playing with Technoculture[END_REF] In other words, the installation tries to deform the reality created by the video game system and its narratives and makes them visible and unnature to the players.

For the players to have easy access and take part in, the game gives had a simple goal and is developed to jump right into the action without any kind of tutorials. The narrative elements inside of this game art project will function on the contrary as the wrappers of the rules; their existence will be a constant reminder of the players, the unnatural existence of the rules in the real world and how the wrappers affect our understanding of the actions that we do in the game world. All those discussions allow us to see further how can we use those elements to construct understanding in the players' minds and how they can create their knowledge by playing this game project.

Virtual and play

To archive these goals, the interactions will lead players to experience the virtual environment thus construct an understanding by themselves.

Video games create a virtual reality in which the individual plays the game. Virtual reality is understood as an environment that is created by a computer or any other media and within which the user has a feeling of being present in the environment [START_REF] Biocca | Communication Within Virtual Reality: Creating a Space for Research[END_REF]. If the feeling of reality is an illusion, then we have to play. We play it to explore, to learn about ourselves and the reality we created. Because the action of the playing is both creative and expressive, it is both a way of being inside the world (virtual or real) and a way of creating sense of it.

This installation fosters spontaneous body movements. The decision is aimed to make the action of its players performative and immersive. Within the safe space (or magic circle) [START_REF] Huizinga | HOMO LUDEN : Essai sur la fonction sociale du jeu, 2nd edn[END_REF] of play, this digital art installation also uses some strategies of the video game design to extend its fictional reality created by the technologies. At the same time, the physical interfaces transfer the movements and sensations of its player into virtual reaction within the digital space which gives them an illusionary feeling of being in control. As this work heavily depends on its visitors to carry out its artistic experiences, can we doubt the artists' role and the visitors within the virtual space, and we can question the illusion of being in control in virtual and in reality?

Game art

In our project, the game art is, at the same time, digital installation and also a standalone video game that uses the gameplay as materials of expression inspired by the rule-based system and it has a complete play goal and a ludic side. It is an interactive installation invite to play and invite to explore without the restrictions on serious subjects On one hand, game art opens up the experiences of gameplay and extends the way videogame forms its culture. The game art is free from the framework of video game and its conventional definition; it allows us to blend video game with other artistic mediums, and to explore and create different kinds of expressions. On the other hand, game art gives us two advantages on the exploration of the context of gameplay. One is the direct reaction of the player that shows us how they perceive the game. The other one is the possibility of presenting this project before the public that is not familiar with videogame medium or digital art, and invite them to explore.

2

The gameplay

Rules

In this game art installation, the gameplay is simple. The player tries to touch two pink balls with a balanced rhythm, just like juggling, to control a star icon that moves across the screen, leaving a trace of pinky cream on its path. When the icons of fruits and sweets touch the trace, they get covered with cream; at the same time, the player gains one point. If an icon of fruit or sweet falls out of the screen without having interaction with the traces, the player will lose a point, and the screen will begin to get covered by semi-transparent cream. When the cream covers the whole screen, the game is over (see Fig. 2).

Playing with the players/visitors

During the development, we decided to have relatively simple gameplay but a much more complex visual presentation to play with the perceptions of the players/visitors. To add the narrative complexity in terms of player/visitors interpretations, we chose sexting emoticons2 as they have at the same time basic shapes and colors, and the familiarity of nowadays emojis. Meanwhile, the specific use of certain icons and pairing present sexual subtexts that can be decoded only by those who are familiarized with the grammar of this new language (see Fig 3). To push this idea further, we decided to explore the double sense inside the installation with its physical interface. In the eye of the adults, those two balls-like controllers constantly give them strong hints to connect those elements (both visual and tactile) with sexual representations within their own experiences, thus completely ignoring that the gameplay is about joggling. While for kids, the controllers have been positioned relatively high to block their vision, forcing them to peep through the controllers to play the already visually confusing game (see Fig 4). For them, the gameplay is about finding a balance to continue the game and to get a higher score. In another aspect, the game aims to challenge the perception of the public and evoke different kinds of reactions. Through the visuals and its difficult control system, the game usually provides an awkward situation for the players to question their own understandings and their skills of playing. The feedback of different groups of people who create their own ways of playing, like an emerging gameplay, is the most interesting part of this installation. The players are, at same time, performers, as they interact and exchange with the waiting players and other visitors that are passing by; they create their narratives and own meanings of the game, as they share their stories and game experiences with the public around them.

3

The design of gameplay

How the installation piece invites the players to perform, just like juggling as a form of performance?

The game art invites its players to try and play with the installation like a game without any serious consequence of performance (winning, losing, right or wrong). It presents an experience without deeper meaning or demanding an understanding of the narrative, the players take their action to explore the gameplay with their bodies, thus rendering the game closer to a playing experience and farther from game experience. At the same time, as players became performers, sharing the experiences and the emotions with the visitors around, inviting the audience to keep playing the game, reinvigorating the cycle spectator-performance.

How can artists use those elements to play with players/visitors?

In-game art, the design of the rules are heavily linked with the context of the installation, the cultural and the physical. And at the same time, the rules are the formal instruments that allow the creation and shared identification of the context of the play. Well-designed gameplay can introduce ideas or structures that un-familiar within the understanding of the players. As the context itself is complicated matters depends on the real-world situation, how to balance the way between all the elements in the game art project is the key to create artistic expression.

We aim to create an installation that demands the players create their narrative on the meaning of the gameplay, thus to make a discussion on the elements in the game art project that can provoke the construction of meaning in the perspective of the players/visitors.

4

Understanding a game

Understanding the play

Most of the time, when we talk about understanding a game is to understand its rules. The idea is not to remember every single rule in the game but to create internalized constraints 3 [START_REF] Upton | The Aesthetic of Play. 1 st edn[END_REF] that are sufficient enough to let the players play the game. And the understanding of the game can vary from players to players. As Parlett indicated:

The totality of rules of all but simplest games are not exactly a cloud of unknowing, but could be described as a cloud of fuzzy knowing. [START_REF] Parlett | RULES OK or: Hoyle on troubled waters[END_REF] But the cloud of fuzzy knowing can give us an idea of what the game is and what the game is about.

For a video game, the situation is more complex. Because not only the rules are not written in natural language and always hidden from the players. For this reason, they have to play the game to understand how the game works, thus understanding the meaning of the game. Except for the rules, there are a lot of other elements function in the game space, these elements usually work as guidance for helping the player to construct internal constraints thus allow them to play it. Or they bring many more meanings to the game more than what the rules can tell.

For discussing this subject, we decided to create visual and audio elements that much more pronounced than its simple gameplay that should be understandable by the majority of the players. When they play the game or watch others play, they should have a comprehension of what the game is base on their way of perceiving pieces of information. Is it by experiencing the game, by reading the subtext of the visuals, by the reaction of others or something more personal, or are they the socalled 云玩家 Cloud Gamer 4 who define a game by perceiving the experiences of others without even play the game themselves?

Shared experience

When we human play (aside from the occasional game of solitaire), we play together..

.When playing together, you and your fellow players take in-game actions that have real consequences for one another's moment-to-moment experience, as

well as consequences for one another's in-game virtual bodies and selves. Thus for us games provide us with opportunities for both sociability and social play. [START_REF] Isbister | How Games Move Us: emotion by design[END_REF] Even though as a portrait by the media today, gamers seem always to play alone before their digital screens.

Video games have had a certain social spectating element to them from their inception. In the early days of arcade games, people would gather around the person playing the game to see how they were doing and to cheer them on. [START_REF] Sjöblom | Why do people watch others play video games? An empirical study on the motivations of Twitch users[END_REF] Or later the development of LAN based or online multi-player games still encourage share videogame experiences. The social aspect of play has a deep meaning in the experiences of play even when playing a single-player game alone. We share our experiences on forums or other social media, we watch other players play on live steaming such as Twitch, and we shared game experiences and studies on gaming journals or the channel of Youtubers. All the information and experiences we shared profoundly affect how we perceive the game and how the general public has received the game. The shared experience becomes one of the essential traits of video game consumption, which differs from other cultural industries' products. Even if games respond to the legitimation chain, in which the public perception of worth determines the value [START_REF] Bouquillion | Diversité et industries culturelles, 1st edn[END_REF], the shared experience of video games is built upon an asymmetrical experience, from the players, and the audience as well.

In this project, we intend to create a social play similar that based on the interpretation of the meaning and the rules of the game. The installation is trying to imitate an arcade game but in a situation completely different. While we committed to the form of arcade games, they are inspired by complicit formal 5 artists and dedicated to investigating and demonstrating the techno-cultural context that shapes the interpretation of form, [START_REF] Schrank | Avant-Garde Videogames: Playing with Technoculture[END_REF] or in other words the understanding of video games medium as a whole. We create the project with conflicting senses and various strategies (for example, presenting visuals of sexual subtexts in a family-friendly and artistic space.) to discuss our understandings of the videogame as a medium. At the same time, it discomforts players/visitors when they are searching the meaning of the game and show them the ubiquity of information that exists in our daily life that distorts our view of a medium rather than experience it by ourselves.

5

The exploration First, we are interested in the creation of visual vocabularies anchored in the evolution of technology and methods of communication that have become both understood by a broader population, across countries and languages; and also complex by the redesignation of icons and meanings, like a new grammar.

As a starting point, we examined the example of the Isotype6 language, born from the industrial and economic revolution of the early 20 th century, from the need to create a system of communication that could be quickly recognizable in a globalizing world. In its visual Autobiography From hieroglyphics to Isotype, Otto Neurath's mentions his intention of creating this system for helping workers (the broader public) to become aware of the economic reality. [START_REF] Neurath | From Hieroglyphics to Isotype: A Visual Autobiography[END_REF] In our project, the exploration of visual vocabularies is an attempt to help people to be aware of the reality of the techno-culture today.

Second, we question the relationship between the body and the machine through the exploration of possible and meaningful interactions. On one side, we look to explore the way interfaces aim to handle the functional and technical requirements of the game.

On the other side, we aim to visualize the impact of the interfaces on the body and how the interface configures the exchange game-user-game.

The design of stressless, enjoyable, or even invisible interfaces has been the discipline ideal for decades. Interfaces have aimed to create versatile exchanges of dialogues between computers and users, particularly in the case of games, for which the effectiveness of the interface is not judged by the effortless operation, but quite the opposite, as acknowledged by Don Norman [START_REF] Norman | JND[END_REF]. For video games, interfaces have merged into the artistic practice as our interaction with the technology become more complex, and our desire to immerse ourselves in virtual space grows. [START_REF]Brief History of UI in Video Games[END_REF] This game art presents an interesting opportunity to experiment this kind of dialogue and help us to learn to control the artificial body inside the virtual space, at the same time, it tears up the disguise of the surface presentations to show us the discomfort distance between our body and the virtual game space.

Finally, we want to explore video game reception and preconceived ideas, in general, but also the public response and its reactions towards mature themes, particularly hidden by colorful and family-friendly visual and sound codes.

In a study of NYU School of Medicine in 2018 argues that humans recognize what they are looking at by combining current sensory stimuli with comparisons to images stored in memory. [START_REF]Past experiences shape what we see more than what we are looking at now[END_REF] For this reason, our perception of information is influenced more by past experiences than by newly arriving sensory input from the eyes. Is this how we understand the videogame's gameplay? How much the media and technologies around us altered our perception of the world, and how can we find the meanings hide behind the visual presentations?

To discuss the precedent questions, Huge Balls focalized on the visual language of emoticons, especially to sexting dynamics, because we consider it has stabilized, with a grammar that allows communicating efficiently in a complex array of meaning where the connotation is far more important than the denotation. The visual treatment of the icons and its selection responds to the third interest, a joyful and family-friendly game that plays around the ambiguity of reading and the interpretation of public, supported heavily in the connotation process. The visual approach is reinforced by the sound design, re-signifying familiar sounds like the ice cream car's melodies. The gameplay proposed by the game look to address the user-game questions. The game is played by interacting with the balls; the juggling in the physical interface corresponds to the virtual space. The players have to move the balls to interact with the objects present in the screen; the result of the interaction forces the body of the gamer to adapt uncomfortable positions. The size of the exhibition plays around the concept of miseen-scè ne of gamers, aiming to expand the game to a multidimensional experience, not limited to visuals, and sound, but also related to touch and the social aspect of gaming.

Fig 1 .

 1 Fig 1. Huge balls in the exhibition Jonglopolis at the Carreau du Temple in Paris in 2018.

1

 1

Fig 2 .

 2 Fig 2. Huge balls version.2 in the exhibition Malakoniarof in Malakoff, 2018.

Fig 3 .

 3 Fig 3. The visual elements inside Huge balls.

Fig 4 .

 4 Fig 4. The installation of Huge balls version.2 in Malakoniarof 2018

A game art group based in Paris, composed of three artists/researchers of EnsadLab (Art & Design Research Laboratory at Ensad): Daniel Pata, Pierre emm and Guofan Xiong.

A representation of a facial expression such as a smile or frown, formed by various combinations of keyboard characters and used to convey the writer's feelings or intended tone.

"Internalizing external constraints." The idea is that as we learn to play a game we take rules that are part of the external constraint set (constraints imposed by outside force) and construct internal analogues of them.

云玩家(Yunwanjia or Cloud Gamer) is a Chinese Internet slang. It refers to the people who judge or critique a video game by watching others play, but never play themselves.

The complicit formal avant-garde does not advance specific mediums. On the contrary, it questions whether videogames or any other art medium (painting, film, video, and so on) are indeed unique mediums… Complicit formal artists still pursue art for art's sake, yet are mischievously liberal and humorous in what they consider to be art, because they have learned from the failures and successes of the historical avant-garde. (Schrank, B. Bolter, D, J.: Avant-Garde Videogames: Playing with Technoculture, pp.23)

Isotype (International System of Typographic Picture Education) is a method of showing social, technological, biological, and historical connections in pictorial form. It consists of a set of standardized and abstracted pictorial symbols to represent social-scientific data with specific guidelines on how to combine the identical figures using serial repetition.


Bénédicte Lebret
email: benedicte.lebret@inrae.fr

Bénédicte Lebret Local

Local pig breeds in France: Research studies focusing on quality of pork and products

come


Aline Courie Lemeur

Delphine François-Philip De Saint

Leadership style and motivation of care workers: the case of health networks in France

Keywords: Motivation, healthcare, network, care workers, leadership

The Covid19 pandemic has shown that the ingenuity of care workers has been pivotal in helping keep the health organizations afloat in France. This is not new and we have seen it many times in previous health or social crises, where the ingenuity of care workers has contributed to ensure rapid care. The Covid19 pandemic has merely confirmed it once again. In this paper, we seek to understand what motivates care workers in their jobs to come up with ingenious solutions and get around problems encountered and the factors that smash their motivation and inventiveness to deal with problems. In particular, we seek to understand whether their involvement in strategic decision-making in healthcare organizations could affect their motivation. The aim is to understand how the leadership style of executives in health authorities and healthcare networks can affect the motivation of health workers.

To explore this question, we examine the case of health networks in France that have undergone successive restructurings initiated by the health authorities and we are particularly interested in the motivation of care workers working within health networks during these restructurings. We develop a theoretical framework around the leadership style and its impact on the motivation of actors in organizations. We seek to provide recommendations regarding the leadership style that would be most conducive to improving the motivation of care workers in French healthcare organizations.

Introduction

The field of health care in France, and in particular hospitals, has undergone numerous reforms over the last few decades with a view to modernizing the public service. The chronic shortage of financial and human resources, the need for comprehensive and multidisciplinary management for complex medical cases, combined with an increasing diversity of management protocols, make it necessary to carry out profound transformations in healthcare field. The health crisis linked to Covid-19 has further demonstrated, amplified and highlighted this.

Faced with these multiple challenges, the public authorities regularly carry out restructuring movements aimed at rationalizing health expenditure and the supply of care. These are a source of profound organizational changes. Admittedly, whether they result in success or failure, changes are inherent to the evolution of an organization and remain 'varied, numerous, increasingly complex, leading to multidimensional effects' [START_REF] Bareil | Démystifier la résistance au changement : questions, constats et implications sur l'expérience du changement[END_REF]; giving rise to numerous psychological states and reactions from the actors (Philip de Saint Julien, 2018). Indeed, public authorities rely on rigid regulatory and normative frameworks and adopt a top-down approach, while taking into consideration the constraints of economic performance, and while dealing with professional and institutional silos specific to health organizations. This makes it difficult to adopt changes designed unilaterally by health authorities and imposed on health organizations and care workers.

A number of studies and writings have been published over the past thirty years, denouncing the negative impact of the so-called "top-down" approach adopted historically by the institutional authorities in France. But despite decades of scientific production advocating collective action to reshape the field of healthcare, and despite attempts to do so by decisionmaking authorities, these same issues remain relevant. The field of healthcare is facing a "disenchantment" of the different actors, on both patients and care workers part, characterized by a deterioration in working conditions, a continuous reduction in the supply of care, and a constant tension in the hospital system. Also characterized by a strong and specific identity dimension [START_REF] Sainsaulieu | L'identité au travail[END_REF][START_REF] Sainsaulieu | L'identité au travail[END_REF], the actors in the healthcare field, particularly the nursing staff, are experiencing greater uncertainty and professional stress; they are subject to injunctions that are 'increasingly paradoxical between the imperatives of management and the imperatives of care, in an increasingly reticular organization that results in multiple bricolages' [START_REF] Bourret | Encadrer dans la fonction publique hospitalière : un travail de lien invisible[END_REF]; they encounter role ambiguities and role conflicts [START_REF] Kahn | Organizational stress: studies in role conflict and ambiguity[END_REF]. The care worker is thus the 'secant marginal' [START_REF] Crozier | L'acteur et le système[END_REF], the actor involved in several systems of action, interacting with each other.

In this article, we question the design of change projects initiated by public authorities in the French healthcare field, the leadership style that accompanies their deployment, as well as the motivation of care workers to adopt it in healthcare organizations. We are particularly interested in health networks in France. We focus on the behavior of care workers in health networks during the deployment of restructurings initiated by the health authorities. We try to understand what motivates them in their work to find ingenious solutions and work around the problems encountered and the factors that break down their motivation and inventiveness. In particular, we seek to understand whether their involvement in the design of the organizational changes they will be required to adopt might affect their motivation. The aim is to understand how the leadership style that accompanies the design and deployment of organizational change in the health field could improve the motivation of care workers and the action of health organizations?

The context of health networks in France

The origins of health networks in France go back to the beginning of the 20th century, when they were set up to treat tuberculosis patients. However, it was in the 1970s that we witnessed the birth of the first network organization between field workers and hospitals, as part of the reform of psychiatry which established sector psychiatric teams. At the beginning of the 1970s, gerontological networks aimed at keeping elderly people at home also appeared. Subsequently, the concept was extended to other pathologies such as AIDS, drug addiction, palliative care, oncology, perinatal care, diabetes, etc., hence the general term "health network". The health network has an associative legal status (Law 1901). It is headed by a director and relies on a multidisciplinary team, including doctors, nurses, psychologists, and sometimes a social worker, etc., to ensure the coordination of care around the patient maintained at home. It supports the attending physician and constitutes a bridge between town medicine and hospital medicine. The health network thus makes up for a weakness in the French health system: the hospital-city link.

However, despite its proven usefulness, the health network has been at the heart of several successive restructuring projects since the 1990s aimed at modernizing the French health system, which is faced, on the one hand, with a shortage of public financial resources and, on the other hand, with the growing complexity of medical treatment and the shortage of specialized human resources. An official report published in 2012 recommended the pooling of single-theme health networks (particularly cancer, gerontology and palliative care) into a single multi-theme network. In 2016, the law n° 2016-41 of 26 January dedicated to the modernization of the French health system then created the complex pathway coordination mechanism known as the Territorial Support Platforms ("Plateforme Territoriale d'Appui", PTA). This system is supposed to absorb all the territorial medical and medico-social coordination structures, including the health networks. Then the Coordination Support Facilities ("Dispositif d'Appui à la Coordination", DAC) were created, with a view to absorbing the PTAs and all the structures linked to the coordination of care. This research focuses on the perceptions of field actors and care workers when the above-mentioned projects were initiated.

When the health authorities introduced the various restructuring projects mentioned above, a feeling of injunction was very frequently reported by care workers and attributed to several factors. While some care workers justified it by the concentration of financial resources for health structures in the hands of the Regional Health Agency, others explained it by the constant reduction of budgets allocated to health networks despite the increase in the number of patients being treated. Some others attributed it to the obligation to extend their territorial coverage and to move towards other themes, which was perceived as a devaluation of the specificities of the territories and themes. Some care workers consider that the health network reflects the needs of its territory and any institutional injunction at this level is perceived as inappropriate [START_REF] Courie-Lemeur | La gouvernance d'une fédération de réseaux : le cas de la Fédération des Réseaux de Santé Gérontologiques d'Ile-de-France[END_REF]. Furthermore, some care workers attribute the feeling of injunction to the obligation to carry out the change project within a specific timeframe; others explain it by the posture of the health authorities and their way of steering the change project. The health authority's poor support for the change, its lack of transparency and its attitude suggesting favouritism according to the territories and personalities of the network actors were also generally denounced. Also, some care workers justified the feeling of injunction by the inconstancy of the health authorities' projects. The succession of restructuring projects (some of which are not completed even before new ones arrive) is perceived as a sign of instability in the public authorities' project. Some even consider that the health authorities are trying to make the health networks shoulder its failure as a regulatory body and its posture towards the health networks is presented as a discouraging factor. Others described its posture as lenient in the past, even lax and rather police-like today. They justified this change in posture by the current shortage of public financial resources and its lack of understanding of the reality on the field [START_REF] Courie-Lemeur | Les réseaux de santéles enjeux de la pérennité[END_REF].

In an attempt to understand the interaction between the leadership style of health authorities and the motivation of care workers in health organizations, such as health networks, we develop a theoretical framework around the levers of motivation and their interactions with the leadership style. We will thus answer our problematic.

Theoretical framework: the leadership of health authorities and the motivation of healthcare workers in France

Leadership refers to the notions of influence and power, where it is presented as a process through which an individual will influence the action of a group to better achieve its objectives [START_REF] Plane | Théories du leadership Modèles classiques et contemporains[END_REF]. A leader's authority and power can have different sources of legitimacy: charismatic, traditional or rational-legal [START_REF] Weber | Economie et Société, 1 ère édition[END_REF][START_REF] Flanchec | Théorie des organizations[END_REF]. These are accepted because of the power of roles, gradual and routine commitment and/or psychological and situational factors. They are based on formal resources but also on informal resources such as the control of one or more areas of uncertainty: relations with the environment, control of information, a degree of competence and/or the use of institutional or organizational rules [START_REF] Crozier | L'acteur et le système[END_REF]. The leader ultimately works to influence and motivate others to contribute to the success of an organization of which they are members, or even of a project or mission [START_REF] House | Culture, Leadership and Organizations[END_REF][START_REF] Boucher | Vous avez dit leadership ![END_REF][START_REF] Cristol | Leadership et management être leader, ça s'apprend ![END_REF][START_REF] Garcia | Le génie du leadership[END_REF].

The leader develops power over others, but according to Crozier [START_REF] Boucher | Vous avez dit leadership ![END_REF], this power can be multiform and can act on the motivation of the actors subject to his leadership. Thus the leader can be 'authoritarian' by adopting a directive approach. He can be 'democratic' by being concerned with the interaction between actors and by soliciting their participation and involvement in decision-making. It can be 'lax' by not giving directives.

They can be 'exploitative authoritarian' by not trusting, remaining distant and inspiring fear. They can be 'paternalistic authoritarian' by being benevolent, even if they do not trust and inspire fear. He can be 'consultative' by building on the relationship of trust and having a developed relationship with his subordinates. They can be 'participative' by building a real team spirit and strong trusting relationships. They can be 'compromise-seeking' by maneuvering to reconcile the needs of individuals with the challenges of productivity. They can be 'social' by prioritizing the human aspect and being concerned with social relations, creating a good atmosphere and reducing conflict. It can be 'integrative' by working to build trust, by seeking to improve motivation and involvement of the actors, while defining a common objective, with a view to increasing productivity. He can be 'autocratic' by adopting an authoritarian style, focusing on productivity and marginalizing the needs of individuals. They can be 'laissez-faire' by remaining in the background and disinterested in both individuals and production [START_REF] Plane | Théories du leadership Modèles classiques et contemporains[END_REF][START_REF] Boucher | Vous avez dit leadership ![END_REF][START_REF] Dejoux | Du manager agile au leader designer[END_REF].

Several currents have followed one another since the beginning of the 20th century to analyze the notion of leadership, such as the theory of personality traits, which focuses on the qualities and traits linked to the personality of the leader [START_REF] Plane | Théories du leadership Modèles classiques et contemporains[END_REF][START_REF] Kirkpatrick | Leadership: do traits matter?[END_REF][START_REF] Golberg | The Structure of Phenotypic Personality Traits[END_REF]; or behavioral theory, which seeks to understand the link between the leader's behavior and his or her leadership style [START_REF] Plane | Théories du leadership Modèles classiques et contemporains[END_REF][START_REF] Boucher | Vous avez dit leadership ![END_REF][START_REF] Dejoux | Du manager agile au leader designer[END_REF]; or even contingency and situational theory, which addresses the link between the context in which the leader operates and his or her leadership [START_REF] Hersey | Management and Organizational Behavior, Utilizing Human Resources[END_REF][START_REF] Garcia | Le génie du leadership[END_REF][START_REF] Kets | La face cachée du leadership[END_REF]. This leads to several leadership styles, which may impact differently on the motivation of the actors involved in the action.

Leadership style in healthcare field in France

In the healthcare field in France, as in the whole public sector, the leadership of institutional decision-makers is mainly a top-down leadership linked to a formal authority generating a subordination link, and not a leadership emanating exclusively from the qualities of the leader and the recognition by others of his or her characteristics pushing them to follow him or her voluntarily [START_REF] Dejoux | Du manager agile au leader designer[END_REF][START_REF] Garcia | Le génie du leadership[END_REF][START_REF] Cristol | Leadership et management être leader, ça s'apprend ![END_REF][START_REF] Plane | Théories du leadership Modèles classiques et contemporains[END_REF].

For the top-down leadership, legitimacy and power are derived mainly from institutional sources (Ghadiri, Flora & Pomey, 2017;[START_REF] Gravereaux | L'innovation, une (re)structuration de formes organisationnelles hospitalières ? Le cas de deux projets « innovants » au sein d'un groupe de santé privé[END_REF] and hierarchical power. This is accompanied by pyramidal, centralized and top-down norms and organizational forms, with classic management typologies systematizing action and hierarchizing the relationship between actors (Ghadiri, Flora & Pomey, 2017;[START_REF] Gravereaux | L'innovation, une (re)structuration de formes organisationnelles hospitalières ? Le cas de deux projets « innovants » au sein d'un groupe de santé privé[END_REF]. As in armies, according to a principle of 'command and control', it is the leaders who decide and the troops have no choice but to obey. Certainly, there has been some alleviation with the emergence of the school of human relations and the generalization of the concept of management, which advocates that 'it is better to give desire than to impose'. However, inspiration and impetus continue to come from above [START_REF] Riveline | Le management la tête en bas[END_REF]. By defending this way of working, decisionmakers are reproducing entrenched organizational routines, but they are also defending their power, even if this is at the expense of agility.

But when innovation takes place at the interfaces of highly institutionalized contexts such as healthcare, the creation of innovative spaces should respond to three key processes [START_REF] Dougherty | Organizing ecologies of complex innovation[END_REF]. First, the knowledge capacities of all stakeholders should be combined. This requires joint regulation that articulates formal and informal knowledge combining the experiences and practices of all necessary institutional and field actors.

On the other hand, the innovations developed should be articulated within the framework of a long-term strategy, while taking into consideration the logic of action [START_REF] Amblard | Les nouvelles approches sociologiques des organisations[END_REF] of all the actors (institutional and field), as well as the challenges of territorialities [START_REF] Maillard | Le partenariat en représentations : contribution à l'analyse des nouvelles politiques sociales territorialisées[END_REF]Grenier & Rimbert-Pirot, 2014). The construction of an articulated set of autonomous rules and joint rules by the actors, in declination of institutional regulations and public policies, will allow them to better appropriate them and avoid the loss of meaning (Joffre, 2014).

Finally, action should be taken to renovate public policies by involving a variety of actors throughout the process. This will lead to a renovation of public action to better deal with the fragmentation of the health field, the emergence of new demands, and the need for personalized care [START_REF] Duran | L'Etat et la gestion publique territoriale[END_REF].

In fact, it is a question of renewing the way in which we govern, by modifying the articulation between the power of decisions and the knowledge of the different actors and by challenging the duality between the 'everything regulated by the policies' and the 'let us do it' claimed by certain professionals [START_REF] Moore | Innovations in governance[END_REF][START_REF] Grenier | Apprentissage de la coordination entre acteurs professionnels -le cas d'un réseau de santé[END_REF][START_REF] Grenier | Proposition D'un Modèle D'espaces Favorables Aux Habiletés Stratégiques[END_REF].

To succeed in initiating such transformations, a 'de facto leadership' seems better suited than a 'de jure leadership'. The evolution towards a 'de facto leadership' is more favorable to the development of the strategic skills of the actors and organizations involved in innovations in the health field. It can better contribute to the sustainability of such innovations and to the sustainable transformation of this field.

When leadership is emanating exclusively from the qualities of the leader and the recognition by others, it becomes a "down-top-down" leadership. It becomes above all a skill held by a particular person within a group of individuals, enabling him or her to unite around him or her and to promote the adaptation of action to a given situation [START_REF] Hersey | Management and Organizational Behavior, Utilizing Human Resources[END_REF]. It is the leader's ability to adopt an evolving leadership style, enabling him or her to adapt to a given situation, which will condition the achievement of an organization's objectives and results [START_REF] Garcia | Le génie du leadership[END_REF]. Leadership thus becomes situational [START_REF] Hersey | Management and Organizational Behavior, Utilizing Human Resources[END_REF].

Leadership is then the result of an interaction between the leader, the follower and the situation [START_REF] Kets | La face cachée du leadership[END_REF]. A good decision is therefore not always a rational decision: 'Action must be rapid and therefore irrational so that reflection does not suffocate the motivation necessary for taking action' [START_REF] Geoffroy | Quand l'hypocrisie managériale protège l'organisation[END_REF]. Beyond the qualities and personality traits that enable a person to stand out from the others and to govern, it is his or her behavior with regard to the actors around him or her that will enable him or her to impose himself or herself as central.

For example, a crisis situation requires the leader to manage delicate, sudden and often rapid kinetic issues. They must prepare their staff to think about the unthinkable, to get directly involved and to instill the necessary dynamics to deal with an unprecedented or unforeseen situation. His action must not be content with being technical, anchored in traditional management methods. To prevent the loss of cohesion and to preserve the stability of the organization, the leader must embody a vision, maintain the confidence of the employees and consolidate the identity of the organization. His action is therefore essential to the survival of the organization for which he is the guarantor [START_REF] Lagadec | Gestion de crise : nouvelle donne[END_REF]. Leadership then becomes transformational and focuses on the motivation and development of employees to improve their performance [START_REF] Bass | Leadership and Performance Beyond Expectations[END_REF].

Leadership become then situational and transformational, which is at once 'consultative', 'participative' and 'integrative'. The leader then becomes a conductor, whose prowess lies in his or her ability to synchronize and harmonize the interventions of the various musicians, whose expertise is complementary because of their similarities and/or differences. He is required to give meaning, inspire, federate in a sustainable way and make actions converge to achieve the predefined objective. It feeds and is fed by collective intelligence, defined as the capacity to unite intelligence and knowledge to achieve an objective and as the capacity of a group to ask questions and seek solutions together [START_REF] Zara | Le management de l'intelligence collective M21[END_REF].

Thanks to collective intelligence, it stimulates creativity and innovation [START_REF] Cristol | Leadership et management être leader, ça s'apprend ![END_REF], motivates and retains employees [START_REF] Boudrias | Démystifier les inventaires de personnalité[END_REF], and changes their behavior while giving real meaning to their work [START_REF] Boucher | Vous avez dit leadership ![END_REF].

Forms of collective intelligence appear as soon as, within an organization, the collective use of scattered information held by different individuals is observed. Collective intelligence will then consist of increasing a group's capacity for understanding and action [START_REF] Autissier | Désir de participation et intelligence collective : le cas de l'entreprise Covéa[END_REF]. This approach aims to create a consensus around the collective action to be taken through both individual and collective cognitive processes. A macro-competence is thus formed, an assembly of the organization's collective competences and quite strategic for ensuring its growth and survival.

Depending on the richness of the connections between the neurons, between the actors of an organization [START_REF] Lenhardt | Le management hybride -Mettre le leadership au service de l'intelligence collective[END_REF], the constitution of a collective will, in fact, determine a level of collective intelligence. A zero level corresponds to a perfectly homogeneous collective where the individuals are functionally identical. The level of collective intelligence will be all the higher as the variety of the collective increases, linked to a diversity of statuses, knowledge, skills and professions [START_REF] Bonabeau | Intelligence Collective[END_REF]Géniaux & Mira-Bonnardel, 2003); all the more so as the effectiveness of the group, of the collective, is focused on the overall contribution of the group rather than on individual effort [START_REF] Gunasekaran | The collective intelligence concept: a literature review from the behavorial and cognitive perspective[END_REF].

Improving collective intelligence will result in knowledge management, which implies the need to identify, preserve, value and protect it. The leadership style then becomes a determining factor for the motivation of the actors involved in the action.

Motivation in health organizations

Within an organization, the leadership and management style can be represented as a continuum, between an authoritarian style on the one hand, and a non-directive style on the other: the former seeks to structure its will, to give each person his or her attributions; the latter seeks to establish more interpersonal relations, relations based on trust, by delegating responsibility for activities to the group and/or to individuals. Between these two poles, multiple forms of leadership exist, more or less directive or collaborative (Tannebaum & Schmidt, 1973).

The question of the relevance of the style of leadership, according to the 'maturity' of the actors, in the sense of [START_REF] Hersey | Management and Organizational Behavior, Utilizing Human Resources[END_REF] is, in fact, primordial. The notion of 'maturity' has a particular meaning. Not being defined as a state of equilibrium reached by the individual, as a full physical, intellectual and emotional development, the "maturity" of an actor is a function of two elements: his level of competences, of his knowledge, know-how and interpersonal skills; and his level of motivation, of energy that he is ready to put into his work [START_REF] Hersey | Management and Organizational Behavior, Utilizing Human Resources[END_REF]. Four levels of maturity are possible. Level M1 corresponds to individuals with little maturity, little competence, little motivation: they have a low level of competence for the position held, they know little or nothing about the requirements of their position and are little motivated. Level M2 corresponds to individuals with medium/low maturity, low competence but motivated: they have a slightly better grasp of the requirements of their job, their skills are low but they are motivated. Level M3 corresponds to individuals with a medium/high maturity, low motivation but competent: they master their job, know the expected requirements but have a low level of motivation. Level M4 corresponds to individuals with high maturity, who are both competent and motivated in their work [START_REF] Hersey | Management and Organizational Behavior, Utilizing Human Resources[END_REF].

Depending on the level of 'maturity', in a dynamic approach, leadership must be situational [START_REF] Hersey | Management and Organizational Behavior, Utilizing Human Resources[END_REF] and the art of the leader is to diagnose which mode of leadership the individual, the team needs (Le [START_REF] Flanchec | Théorie des organizations[END_REF].

The effectiveness of a situational leader depends on the development of the people in his or her team, with this development ensuring the success of the group in the long term; it consists of adopting, at a given moment, the style according to the context encountered; it consists of constantly evaluating the 'maturity' of the players, i.e. identifying their degree of competence and motivation; and finally, it consists of creating the conditions that allow the maturity of the players to develop [START_REF] Hersey | Management and Organizational Behavior, Utilizing Human Resources[END_REF].

Table 1 summarizes the motivational levers with regard to the leadership style that we apply to the case of health network actors. Authoritarian style: hierarchical operation and unilateralism in decision-making power -Formal authority with subordination; hierarchical power -Mobilization of "quasi-injunction" / "negotiated injunction"

The health authorities adopt an authoritarian leadership style with the health network.

Restructuring projects for the health network are constructed in a unilateral way by the health authorities. They are imposed on the health network in a top-down manner, given the organization of the French health scheme, which attaches all financial resources dedicated to health networks to the Regional Health Agency (ARS). It is the ARS that decides on their allocation and defines the criteria and conditions to be met in order to benefit from them. This generates a feeling of injunction among health network actors "With the ARS, it's like in the army, they are the ones who decide and we have to obey without flinching (...) it's an injunction, or at least within the network we see it that way"1 "Down-top-down leadership" = "Situational leadership": the leader adopts, in an evolutionary manner, a leadership style adapted to the maturity of the actors

Authoritarian style -maturity level M1: the leader is very task-oriented and not very relationship-oriented; the actors are not very motivated or competent.

The leader prescribes precise directives and instructions, makes decisions; controls the execution of tasks and the results obtained; does not allow room for manoeuvre, autonomy

The leadership style of the health network leader: between authoritarian & persuasive style. Occasionally participative.

The leadership style is defined by the nature of the task.

For issues related to the governance of the health network, as well as strategic decisions within the network or in relation to health authorities and other organizations in the territory, the health network manager adopts a directive style. He or she makes decisions, prescribes precise instructions, and informs team members of the decisions taken.

"It is clear that decisions about the direction of the network and its strategic choices depend on me and the network presidents. The team, I inform them of our choices, that's all. "2 Concerning the issues related to patient care, when the health network director is trained as a doctor, he or she participates in decision-making concerning the patient. He appears to be very relationship-oriented when it comes to developing collaborations with other health organizations in the area to improve patient care, or when he seeks to develop alliances to improve his bargaining power with the supervisory authorities in order to access additional financial resources for his health network. His leadership style is therefore persuasive. "I managed to negotiate with the Regional Health Agency (ARS) and convince them He can also be participative at times, when it comes to decisions related to the functioning of the team or also when collaborating with other health structures. The director seeks to create a friendly atmosphere and encourages interpersonal relations within the team.

"We can only be participative if we want to work together (...) We have created a joint working group, with people from their homes and ours, to build common tools"4 .

Level of maturity of staff in health networks: between levels M3 & M4: the multidisciplinary composition of the health network team and the specialization of its members mean that competence in patient care is strong. The employee has the necessary knowledge, skills and attitudes. They know how to use their basic knowledge or previous experience to ensure the coordination of care around the patient.

His/her motivation is generally strong, because of the meaning he/she gives to his/her work (service to the patient and to society). Their motivation may be hampered by the lack of resources available to them to carry out their work. However, when it comes to regulatory changes, restructuring projects or experiments initiated by the health authorities, the employee expects information to come from the outside, particularly from the manager. They need to be told what to do. His motivation may be weakened by a feeling of incomprehension about his work, by a conflict with the director of the health network, or by the continuous change projects imposed on him by the health authorities. He thinks that the health authorities do not realize the reality of the needs on the ground and that all the attempts to explain them to them for several years have never been successful. "I don't know much about the ARS projects, it's xxxx (director) who deals with that (...). When there is something new and important, he explains it to us."5 "There is nothing we can do about it (...) anyway it won't change anything"6 .

Delegative style -maturity level M4: the leader is not very task and relationship oriented; the actors are motivated and competent.

There is no need to explain objectives and tasks to a competent and motivated team; they are allowed to work autonomously, without having to control and supervise

Conclusion

The health and medico-social sectors in France are constantly being restructured in order to improve patient care while optimizing the use of increasingly scarce specialized financial and human resources. And each time, the restructuring attempts fail to achieve the targeted objectives. Although defensible, these projects are not always unanimously supported by the care workers, and this is generally reflected in the poor success of the projects. The Covid-19 pandemic crisis has shown the flaws in these restructurings and that the reality is still far from the desired Grail.

We have used the case of health networks and the different waves of restructuring they have undergone to explore the impact of the leadership style of the leaders of health authorities and health networks on the motivation of care workers working in these networks. We have attempted to show that a de facto leadership style that is transformational would have a better impact on the motivation of care workers in health networks than a de jure leadership that is exclusively directive.

Such leadership at the level of the health authorities would favor the motivation and involvement of the actors in the field in the formulation of objectives and the deployment of public actions. This would enable the players to understand the meaning of the changes planned by the public authorities and their involvement in such a reflection and in the decision-making process can have a positive effect on their motivation and their support for such projects. And the mobilization of such leadership would be all the more vital as the change desired by the public authorities is of a radical nature.

At the level of health networks, our research has enabled us to observe that the leadership style of managers is de facto and transformational, with a level of maturity of the staff between the M3 and M4 levels. Health professionals in these organizations are generally competent due to their training. However, their motivation may fluctuate: sometimes it is strong because of the meaning given to their work and sometimes it is weak because of the lack of resources available to them to carry out their work or because of the perception of injunction in the change projects imposed on them, or even because of conflicts with the approach of the network director. The leaders of the health networks seem to mobilize persuasive and participative leadership, but particularly when collaborating with other health organizations in the area, or when building alliances to develop negotiating power with the health authorities. However, with regard to the members of their teams, their leadership remains mainly directive and is only participative when making decisions related to the internal functioning of the team. The construction of strategic decisions remains exclusively in his hands, where he makes decisions, prescribes precise instructions, and subsequently informs the team members of the decisions taken. This seems to have a negative effect on the sustainability of their motivation.

Thus, the changes imposed on health organizations seem to impact on the motivation and commitment of health professionals. But if their organizational commitment seems to be diminishing, their commitment at work has been maintained until now because of the presence of 'commitment anchors' (actions, people, ideas, values, etc.) [START_REF] Kouadio | Employés publics dans les environnements hybrides : quelles ancres d'engagement et quelles pratiques de GRH ?[END_REF].). Public service allows for the ideals of equity and social justice to be lived out, for a job to be meaningful and of concrete use in and for society. The meaning and concrete usefulness that they perceive in their job for society reinforces this commitment. But the weight of these anchors seems to be weakening, and the leadership style of health authorities and health network leaders seems to accentuate this.

Table 1 . -Leadership vs. Motivation of health network actors Leadership Leadership vs Motivation Leadership vs. Motivation of health network actors

 1

	"Top-down Leadership" =
	"Authoritarian leadership":
	the leader adopts a single
	leadership style

  We are the only network in the territory that has a social worker post, because I was able to convince the big bosses at the ARS."3

	seeks to create a friendly atmosphere	to fund us a new doctor's post (...).
	Persuasive style -maturity level M2: the leader is very
	task and relationship oriented; actors are low skilled but
	motivated.
	He provides support, fosters good interpersonal
	relationships; provides extensive explanations of the reasons
	and consequences of the goals he has set; encourages the
	individual and the team
	Participative style -maturity level M3: the leader is not
	task-oriented and is very relationship-oriented; the actors are
	competent but not very motivated.
	He encourages exchanges between a competent but
	unmotivated team; listens to and takes into account opinions,

Courie[START_REF] Courie-Lemeur | Les réseaux de santéles enjeux de la pérennité[END_REF]

CourieLemeir (2016)

[START_REF] Courie-Lemeur | La gouvernance d'une fédération de réseaux : le cas de la Fédération des Réseaux de Santé Gérontologiques d'Ile-de-France[END_REF]

Ibid

[START_REF] Courie-Lemeur | Les réseaux de santéles enjeux de la pérennité[END_REF]

ibid


D Brown

Djordje Atanackovic

L Baris

Dr Anneclaire J De Roos
email: aderoos@drexel.edu.

John Spinelli

Elizabeth B Brown

Dalsu Baris

Leslie Bernstein

Parveen Bhatti

Nicola J Camp

Brian C Chiu

Jacqueline Clavel

Wendy Cozen

Silvia De Sanjosé

James A Dosman

Jonathan N Hofmann

John R Mclaughlin

Lucia Miligi

Alain Monnereau

Laurent Orsi

Mark P Purdue

Leah H Schinasi

Guido J Tricot

Sophia S Wang

Yawei Zhang

Brenda M Birmann

Pierluigi Cocco

Pooled study of occupational exposure to aromatic hydrocarbon solvents and risk of multiple myeloma

Pooled study of occupational exposure to aromatic hydrocarbon solvents and risk of multiple myeloma

INTRODUCTION

There is a need for data characterising potential carcinogenic risks from current use chemicals. Exposure to aromatic hydrocarbon solvents is widespread both in certain occupations and in the ambient environment. These chemicals, including benzene, toluene and xylene, occur naturally in petroleum and are also found in a wide variety of petroleumderived products such as vehicle fuels, paints, coatings, resins and adhesives. Benzene is a known carcinogen for its relationship with acute myeloid leukaemia (AML). [START_REF] Loomis | Carcinogenicity of benzene[END_REF] The relationship of benzene with other types of leukaemias and lymphomas is not as well established, but remains of interest due to associations with non-Hodgkin's lymphoma and multiple myeloma (MM) in some studies. Toluene and xylene have been far less studied as potential carcinogens, and much of the epidemiological evaluation of these two solvents is based in occupational cohorts with limited exposure assessment and little individual-level information.

Several case-control studies with detailed data on job histories and workplace exposures of study participants from the general population have examined whether aromatic hydrocarbon solvents contribute to risk of MM. Although these case-control studies include large numbers of MM cases compared with industry-based cohort studies, the statistical power is limited by the low frequency of persons with high-intensity occupational solvent exposure. Pooled studies and meta-analyses of individual, regionally based case-control studies offer promise in summarising risk factors for a rare cancer like MM.

To investigate a potential role of aromatic hydrocarbons in causation of MM, we pooled data from multiple case-control studies participating in the International Lymphoma Epidemiology Consortium (InterLymph). An earlier consortium-based pooled analysis of five case-control studies found a 38% increased risk (95% CI 0.96 to 1.85) for employment in occupations with high exposure to any organic solvent, [START_REF] Perrotta | Multiple myeloma and occupation: a pooled analysis by the International Multiple Myeloma Consortium[END_REF] demonstrating the potential use of our consortium-based approach. Our research on specific solvents includes nine studies with information on lifetime occupational history, comprising 2854 cases and 10 743 controls.

METHODs

Study population

The study population was pooled from case-control studies of MM participating in InterLymph. A study was eligible for inclusion in this pooled analysis of solvents if its protocol included collection of information on lifetime occupational history. A summary of the nine participating studies [START_REF] Demers | A case-control study of multiple myeloma and occupation[END_REF][START_REF] Baris | Occupation, pesticide exposure and risk of multiple myeloma[END_REF][START_REF] Costantini | Risk of leukemia and multiple myeloma associated with exposure to benzene and other organic solvents: evidence from the Italian Multicenter case-control study[END_REF][START_REF] Cocco | Occupational exposure to solvents and risk of lymphoma subtypes: results from the Epilymph case-control study[END_REF][START_REF] Orsi | Occupational exposure to organic solvents and lymphoid neoplasms in men: results of a French case-control study[END_REF][START_REF] Ghosh | Multiple myeloma and occupational exposures: a population-based case-control study[END_REF][START_REF] Gold | The relationship between multiple myeloma and occupational exposure to six chlorinated solvents[END_REF][START_REF] Purdue | Variation in innate immunity genes and risk of multiple myeloma[END_REF][START_REF] Nuyujukian | Medication use and multiple myeloma risk in Los Angeles County[END_REF] is shown in table 1.

The case-control studies enrolled histologically confirmed incident primary diagnoses of MM (ICD-O-3 973, ICD-9 203) that occurred during the respective enrolment periods. Controls were identified in the general population or from participating hospitals, and were frequency-matched or pair-matched to the cases by variables including age, sex and, in some studies, study centre or race (table 1).

We obtained data on occupational history from each of the participating studies, including, for each job reported by a subject, the job title, industry, dates of employment and self-reported exposures. We also requested, where available, solvent exposures that were assessed by experts (eg, industrial hygienist) in the original, individual studies. Subjects who never held a job outside the home were excluded from the database (<1% of subjects), as were 138 subjects with missing data on education or race. The final analytical dataset included 2854 cases and 10 743 controls.

Exposure coding

All exposure coding for the pooled study was conducted blinded to case status. We linked subjects' occupational histories to job-exposure matrices (JEMs) for aromatic hydrocarbons, specifically for benzene, toluene and xylene; these JEMs were developed for, and applied in, previous epidemiological studies. 12 13 In order to link the JEMs, all reported occupations and industries were consistently coded using either US Standard Occupational Classification 1980 and Standard Industrial Classification 1987 codes or the International Standard Classification of Occupations 1968 and Nomenclature of Economic Activities 2000. For each type of solvent, the JEM assigned an exposure probability (the likelihood of exposure) and intensity (the average concentration of exposure), according to the job and industry. Probability levels represented low (ie, possible (1)), medium (ie, probable (2)) and high (ie, certain (3)), and intensity levels represented low (1), medium (2) and high (3). Jobs with no linkage to the JEM were considered unexposed. In some study observations where the job was given but industry was missing, we assigned the job-specific exposure intensity with low probability.

We reviewed JEM-assigned job-level exposure probability in conjunction with additional information from the individual studies on self-reported exposure or expert assessment of exposure, and used those sources to 'correct' the exposure probability. In particular, we focused on increasing the specificity of solvent exposure assignments, by downgrading the exposure probability for a certain job if there was no additional evidence of exposure. We used questionnaire responses about solvents to correct exposure probabilities in four of the nine studies (table 1). For example, an item on the Fred Hutchinson Cancer Research Center-1980s (FHCRC-1980s) study questionnaire asked if the subject was ever exposed to benzene. We reviewed the questionnaire responses for all FHCRC-1980s subjects with JEM-assigned benzene exposure and downgraded the exposure probability for each exposed job (by 1) if the person did not report benzene exposure. In three of the nine case-control studies (L'Etude des Facteurs Environmentaux et Genetique des Lymphomes de l'Adulte (ENGELA), Epilymph, Italian Multi-centre), experts had assessed solvent exposures in the original studies, based on detailed job-specific questionnaires answered by the study participants. For these studies, we corrected the JEM-assigned probability by downgrading probability (by 1 or 2) if the experts had assessed a lower probability than the JEM. Only two of the nine studies did not have any additional solvent-related information for correction of exposure probability, and for these studies, the JEM-assigned probability was retained.

We evaluated solvent associations with MM according to the highest intensity of exposure across all jobs (categories of low, medium, high), the duration of exposure across jobs (categories of ≤10 years, 11-20 years, >20 years) and the cumulative intensity of exposure (split by quartiles of the distribution among all subjects). We defined cumulative intensity for each solvent as the job-specific exposure intensity multiplied by job duration, summed across all jobs. Exposure coding in the pooled study was also conducted specifically for jobs with high-probability exposure (probability=3, after correction by self-reported or expert-assessed exposure from the individual studies) and exposure during lag periods of interest (exposure occurring >20 years before MM diagnosis or reference date; exposure within 20 years of MM diagnosis/reference date). Finally, we coded exposure variables limited to jobs held before 1980, a year before the first International Agency for Research on Cancer (IARC) evaluation of benzene, in which the chemical was formally recognised as a carcinogen (a cause of AML). [START_REF]International Agency for Research on Cancer (IARC). Some industrial chemicals and dyestuffs[END_REF] In addition to the individual aromatic hydrocarbons, we coded exposure variables for benzene, toluene, or xylene (BTX) exposure, reflecting exposure to any of the three solvents.

Statistical analysis

We estimated the risk of MM in relation to aromatic hydrocarbon solvent exposures using unconditional logistic regression to produce ORs and 95% CIs, with the unexposed subjects as the referent in each model. We considered two-tailed p values less than 0.05 to indicate statistical significance. When evaluating high-probability exposures, subjects with lowerprobability exposure were retained in the model in a separate category, thereby including the same study population and reference group in each model. Tests for trend across categories of exposure were performed by modelling the intracategory median (of cases and controls combined) as a continuous variable, with values for unexposed participants set to zero. All models included a minimal set of potential confounders: age (<50, 50-59, 60-69, ≥70 years), sex (male, female), education (did not graduate from high school, high school graduate, college graduate), race (white/Caucasian, black/African American, other race, data on race not collected), study (indicator variable for each of the nine case-control studies) and study centre (for studies conducted collaboratively in multiple locations). In separate analyses, we evaluated potential confounding by farming occupation, of concern as agricultural work is arguably the most consistent of suspected occupational risk factors for MM [START_REF] Purdue | Multiple Myeloma[END_REF] and because those jobs were fairly common in the study population (14.3% of cases, 13.2% of controls). Effect estimates were produced for the entire pooled dataset, as well as by sex, age group (<50 years, ≥50 years) and continent (North America and Europe). We conducted analyses limiting to studies with and without exposure 'correction'. We also conducted analyses after excluding one study at a time, to evaluate the influence of any individual study on the results. All pooled data analysis was conducted using SAS V.9.3 (SAS Institute, Cary, North Carolina, USA).

We repeated the main analysis using a meta-analytical approach to formally evaluate heterogeneity of effect among the studies. Effects were estimated by study with adjustment for the relevant covariates and then combined in a random-effects meta-analysis. Metaanalysis was conducted using Stata V.12 software (StataCorp, College Station, Texas, USA).

RESULTS

The 2854 cases were slightly more likely than the 10 743 controls to be coded with any occupational exposure to aromatic hydrocarbons in the pooled study (33.5% of cases, 31.2% of controls; online supplementary table 1). Exposure frequencies were considerably reduced when limiting to high-probability exposure, with 11.1% of controls exposed to any BTX. Exposure frequencies were higher among men than women, in older compared with younger subjects, and among those with low education or black race. Exposure assignments for toluene and xylene were extremely similar; 99.8% of subjects with exposure to xylene were also exposed to toluene, and this was also reflected in a correlation of 0.99 between cumulative intensity of exposure for the two chemicals. There was less overlap with benzene; 82.3% of subjects with benzene exposure were also classified with exposure to toluene or xylene, with correlations of 0.81 for benzene cumulative intensity with either of the other two solvents. The median exposure duration was 13 years for benzene and 10 years for both toluene and xylene. The vast majority of subjects with BTX exposure (96.8%) was exposed in jobs held prior to 1980.

Cumulative intensity of benzene exposure was associated with increased risk of MM (table 2); the association was particularly observed with the highest levels of high-probability exposure. There was 42% increased risk of MM for the highest quartile versus unexposed (OR 1.42, 95% CI 1.08 to 1.86), and the p value for trend across exposure categories was 0.01. The result was somewhat strengthened by inclusion of a model covariate for toluene or xylene exposure (OR 1.52, 95% CI 1.11 to 2.09), but was unaffected by adjustment for farming occupation (OR 1.43, 95% CI 1.09 to 1.87). In analyses of exposure defined based on jobs held before 1980, the risk estimate was slightly higher than in the main analysis (OR 1.54, 95% CI 1.16 to 2.03), although the exposure-response gradient was similar, with the association primarily limited to the highest category of exposure. There was no statistically significant association with benzene exposure intensity or duration (online supplementary table 2), although there was a suggestive trend of increasing risk by duration (p trend=0.05). The results from random-effects meta-analysis (online supplementary table 3) were similar to those from the pooled analysis, with a meta-estimate of 1.63 (95% CI 1.06 to 2.50) for the highest quartile of cumulative intensity of high-probability exposure versus unexposed (compared with OR 1.42 from the pooled analysis). The meta-analysis indicated moderate heterogeneity of the effect among the studies (I 2 =30.5%, p=0.17; online supplementary figure 1). In analyses by lag period (table 3), the association was stronger and the exposure-response trend more apparent for exposure occurring within 20 years of the diagnosis/reference date than for exposure lagged by at least 20 years.

The results for toluene and xylene were very similar to each other due to the overlapping exposure categorisations. For brevity, we highlight the results for toluene in the text. There was a pattern of increasing MM risk with greater cumulative intensity of toluene or xylene exposure (table 2), primarily when considering high-probability exposure. For toluene, there was 63% increased risk of MM for the highest quartile versus unexposed, and a statistically significant trend across exposure categories (p trend=0.0007), although small elevations in the other quartile categories were not statistically significant. The observed association with the highest exposure quartile was only slightly attenuated with adjustment for benzene exposure (OR 1.59, 95% CI 1.18 to 2.15), and there was no confounding by farming occupation. Toluene or xylene exposure based on jobs held before 1980 produced nearly identical associations with MM as the main exposure definition. Highest-intensity exposure and duration of exposure were also associated with increased risk of MM, for the highest categories of high-probability exposure (online supplementary table 2). Random-effects meta-analysis of cumulative intensity exposure (online supplementary table 3) showed similar results to the pooled analysis, with a meta-estimate for toluene of 1.79 (95% CI 1.35 to 2.37) for the highest quartile of high-probability exposure versus unexposed, and no indication of heterogeneity between studies (I 2 =0%, p=0.73; forest plot shown as online supplementary figure 2). As for benzene, analyses by lag period revealed stronger associations for exposures occurring within 20 years of the diagnosis/reference date than for exposure lagged by at least 20 years; nevertheless, there was a significant association with MM in both lag periods (table 3). The results for BTX exposure reflect a combination of the associations with the three individual solvents (tables 2 and 3).

We focused sensitivity analyses on the results for cumulative intensity of high-probability exposure (figures 1 and 2; online supplementary figure 3). Associations were stronger in men than women; however, results for women were based on sparse data. Risk increases were observed in both younger (<50 years) and older age groups. Risk increases were seen in both the six North American and three European studies, although estimates based on the European data were far less precise. Results were not greatly sensitive to exclusion of any one particular study. Positive associations were most reduced with exclusion of the Cross-Canada study, which was composed of only men. The strongest risk increases were observed with exclusion of the two studies lacking information for 'correction' of JEM-assigned exposure (benzene: OR 1.96, 95% CI 1.32 to 2.90; toluene: OR 2.27, 95% CI 1.50 to 3.45), particularly for exposure within 20 years of diagnosis (benzene: OR 2.73, 95% CI 1.61 to 4.64; toluene: OR 3.24, 95% CI 1.93 to 5.45).

DISCUSSION

In our consortium-based pooled analysis of nine case-control studies, we found evidence for increased risk of MM from occupational exposure to aromatic hydrocarbons. These associations were strongest with high probability of exposure and with enhancement of exposure specificity using subject-specific information from their occupational histories. There was negligible heterogeneity between studies of the effects associated with toluene and xylene exposures, and these associations were observed within multiple subgroups of the study population and across all analyses, further indicating consistency. A moderate heterogeneity across studies was observed for the association with benzene. The overlap between specific solvent exposures was substantial, limiting interpretation.

The objective of our pooled analysis approach was to enable a statistically well-powered examination of infrequent occupational solvent exposures in relation to a rare cancer. Three of the case-control studies included in our pooled analysis had previously examined occupational benzene exposure. The Italian Multicentre study (263 cases, 1100 controls) found increased MM risk for medium-intensity/high-intensity benzene exposure (OR 1.9, 95% CI 0.9 to 3.9), and the risk estimates were more elevated with at least 10 years' exposure duration (OR 4.1) or latency (OR 2.3). [START_REF] Costantini | Risk of leukemia and multiple myeloma associated with exposure to benzene and other organic solvents: evidence from the Italian Multicenter case-control study[END_REF] Cocco et al observed non-significant 40% increased risk of MM in association with benzene exposure in the Epilymph study (277 cases and 2460 controls). [START_REF] Cocco | Occupational exposure to solvents and risk of lymphoma subtypes: results from the Epilymph case-control study[END_REF] There was no association in the ENGELA study conducted in France (56 cases, 313 controls). [START_REF] Orsi | Occupational exposure to organic solvents and lymphoid neoplasms in men: results of a French case-control study[END_REF] Toluene and xylene were associated (without statistical significance) with increased MM risk in the Italian Multicentre study with longer duration exposure, [START_REF] Costantini | Risk of leukemia and multiple myeloma associated with exposure to benzene and other organic solvents: evidence from the Italian Multicenter case-control study[END_REF] but there was no association in Epilymph. [START_REF] Cocco | Occupational exposure to solvents and risk of lymphoma subtypes: results from the Epilymph case-control study[END_REF] Clearly, our analysis of nine studies had adequate statistical power to detect modest associations and to characterise heterogeneity of the effect between case-control studies conducted in various regions of North America and Europe, improving on individual, regional analyses. The previously published results differ in some instances from our estimated study-specific effects (online supplementary figures 1 and 2), primarily due to disagreement between the JEM used in our study and expert-assessed exposure in the individual studies. We capitalised on such disagreement to improve exposure coding in our pooled study, as described below.

A concern with the use of JEMs is that persons in the same job and industry receive the same exposure assignment, whereas in reality, exposures may differ between people in the same job based on different duties or workplace practices. We strategised to decrease misclassification in our pooled study by enhancing the specificity of exposure coding. In general population-based case-control studies with low exposure prevalence (as for occupational solvents), even small numbers of individuals incorrectly classified as exposed can result in bias that attenuates effect estimates towards the null value. 16 17 To that end, we used questionnaire data and expert assessment of solvents from the individual studies to 'correct' the JEM-assigned exposure probability, for a more stringent (specific) definition of exposure in the pooled study. The increased risks with aromatic hydrocarbons were essentially only observed with the 'corrected' high-probability exposures. Furthermore, the associations were strongest when limiting to the seven studies with information available for exposure correction. The pattern of increasing strength of association with enhanced specificity of exposure coding strengthens the plausibility of our findings; however, it is impossible to know whether the increased ORs are due to a more specific (causal) effect or introduced bias from using self-reported exposures. Self-reporting of exposure can suffer from misclassification due to poor or biased recall. We are assured by the fact that such issues are unlikely to have affected subjects' reporting of job title, [START_REF] Teschke | Occupational exposure assessment in case-control studies: opportunities for improvement[END_REF] used as the primary basis for exposure coding in our study by linkage to the JEM, despite possibly affecting the self-reported exposures that we used for enhancing the specificity of exposure assignments. We are further assured that the associations we observed are not entirely due to misclassification or bias from self-report, as we did not observe a positive association in every study with exposure correction based on self-report (such as for benzene exposure in the FHCRC-1980s study), and, likewise, there were positive associations observed in studies without self-reported information available for exposure correction (ie, with probability based on the JEM alone, as for benzene and toluene exposure in the Population Health study).

In their 2017 assessment of benzene, IARC found sufficient evidence that benzene causes AML/acute non-lymphocytic leukaemia, and limited evidence for a relationship between benzene and other lymphohematopoietic cancers, including MM. [START_REF] Loomis | Carcinogenicity of benzene[END_REF] IARC noted that most cohort studies found no association with MM 18 ; however, one meta-analysis found that the association between benzene and MM was strongest in cohort studies with presumably higher-quality case classification, exposure assessment and greater exposure contrasts. [START_REF] Vlaanderen | Occupational benzene exposure and the risk of lymphoma subtypes: a meta-analysis of cohort studies incorporating three study quality dimensions[END_REF] While our pooled study results provide some support for a causal association between benzene and risk of MM, inconsistencies limit the strength of our conclusions. The association was found only at the highest levels of exposure and was moderately heterogeneous between the studies. In addition, there were null or merely suggestive effects observed in analyses of exposure intensity and duration metrics, and with a longer lag between exposure and diagnosis. Nevertheless, there was an apparent exposure-response gradient with benzene exposure occurring less than 20 years before diagnosis.

The stronger association with more recent exposure is some-what consistent with observations in cohort data in which relative risks of benzene in relation to MM declined with longer follow-up (eg, >20 years) in some studies, particularly when exposure had terminated decades earlier. [START_REF] Infante | Benzene exposure and multiple myeloma: a detailed meta-analysis of benzene cohort studies[END_REF] This finding may imply a late-stage biologic mechanism for benzene-induced myeloma-genesis, such as through altered immunity. Such a mechanism is supported by studies that observed immune effects in workers following exposure, such as decreases in circulating leucocytes and antibodies, [START_REF]Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological profile for benzene[END_REF] and lowered CD4 + :CD8 + ratio. [START_REF] Lan | Hematotoxicity in workers exposed to low levels of benzene[END_REF] Furthermore, well-documented increases in MM incidence among patients with AIDS and certain autoimmune diseases [START_REF] Purdue | Multiple Myeloma[END_REF] identify immune alteration as an important biologic mechanism in MM aetiology. Benzene alteration of immune competence could theoretically promote tumour development, acting at a later stage than initiating genotoxic changes (which may also be induced by benzene). [START_REF]IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Chemical agents and related occupations[END_REF] An alternate explanation for associations limited to more recent exposure is competing risks, if subjects exposed to aromatic hydrocarbons were more likely to die earlier, from causes other than MM. Finally, enhanced or biased reporting of more recent exposures may have resulted in stronger associations with the shorter lag.

Toluene and xylene were individually evaluated in the IARC monograph programme in the late 1990s, by which each solvent was categorised as group 3, 'not classifiable as to its carcinogenicity in humans,' in part due to inadequate evidence in humans. 23 24 Epidemiological studies have been particularly lacking for toluene or xylene in relation to MM. The evidence for a potential role of toluene and/or xylene in causation of MM was moderately strong and consistent in our pooled study. There was little heterogeneity of the effect among the studies, and the associations were robust to exclusion of any one of the studies. Positive associations were observed with cumulative intensity of exposure, as well as with the metrics of exposure intensity and duration. Furthermore, increased risks were observed with both distant exposure (>20 years) and exposure more proximal to diagnosis (≤20 years), perhaps suggesting biologic mechanisms acting in both early-stage and later-stage myelomagenesis.

In conclusion, our study adds important evidence for a role of aromatic hydrocarbon solvents in causation of MM. The difficulty in disentangling individual compounds in this group, in addition to a lack of data on potential carcinogenicity of toluene and xylene, in widespread current use, underscore a need for further epidemiological evaluation.

Key messages

What is already known about this subject?

•

Benzene is a carcinogen known for its relationship with acute myeloid leukaemia; however, its association with other lymphohaematopoietic cancers is less clear. Several previous studies and meta-analyses have observed an association between benzene exposure and risk of multiple myeloma, but the evidence has been inconsistent. Other aromatic hydrocarbon solvents, such as toluene and xylene, have been little studied as potential human carcinogens.

What are the new findings?

• Exposure to each of the aromatic hydrocarbons was associated with increased risk of multiple myeloma. The results for toluene and xylene were rather consistent between studies included in our pooled analysis and in various subgroups of the study population, including men and women, and older and younger persons. A similar association with benzene was moderately heterogeneous between the studies. For all three solvents, associations were strongest for exposure occurring within 20 years of diagnosis, compared with exposure lagged by more than 20 years.

How might this impact on policy or clinical practice in the foreseeable future?

•

Our study adds important evidence for a role of aromatic hydrocarbon solvents in causation of multiple myeloma. The difficulty in disentangling individual compounds in this group hinders conclusions for effects specific to any one of the compounds. Toluene and xylene are in current widespread use, and a lack of data on these compounds, coupled with our suggestive findings, begs for further epidemiological evaluation to support assessment of policy.

Figure 1 .

 1 Figure 1. Association of benzene exposure with risk of multiple myeloma (cumulative intensity of high-probability exposure, highest quartile vs unexposed). ENGELA, L'Etude des Facteurs Environmentaux et Genetique des Lymphomes de l'Adulte; FHCRC-SEER, Fred Hutchinson Cancer Research Center-Surveillance, Epidemiology, and End Results; FHCRC-1980s, Fred Hutchinson Cancer Research Center-1980s; LACCMM, Los Angeles County Case-Control Study of Multiple Myeloma.

Figure 2 .

 2 Figure 2. Association of toluene exposure with risk of multiple myeloma (cumulative intensity of high-probability exposure, highest quartile vs unexposed). ENGELA, L'Etude des Facteurs Environmentaux et Genetique des Lymphomes de l'Adulte; FHCRC-SEER, Fred Hutchinson Cancer Research Center-Surveillance, Epidemiology, and End Results; FHCRC-1980s, Fred Hutchinson Cancer Research Center-1980s; LACCMM, Los Angeles County Case-Control Study of Multiple Myeloma.

Table 1

 1 Studies included in the InterLymph pooled study of occupational solvent exposure

	ENGELA	L'Etude des Facteurs	Environmentauxet	Genetique des	Lymphomes de	l'Adulte (ENGELA)			France: Bordeaux,	Brest, Caen, Lille,	Nantes, Toulouse				2000-2004	108	478	Hospital		Pair-matched by age,	sex, study centre				59.0 (9.0)		63.0	36.5			Not collected	Expert assessment:	benzene, toluene/	xylene
	FHCRC-SEER	Fred Hutchinson	Cancer Research	Center-	Surveillance,	Epidemiology,	and End Results	(FHCRC-SEER)	USA: Michigan,	Washington State					1999-2002	177	481	Population		Frequency-	matched by age,	sex, study centre			59.4 (10.3)		52.0	11.6			76.2	None
	Epilymph	Epilymph							Europe: Czech	Republic,	France,	Germany,	Ireland,	Italy,Spain	1998-2004	278	2464	Population or	hospital	Frequency-	matched by	age, sex, study	centre		56.8 (15.8)		53.9	46.3			Not collected	Expert	assessment:	benzene,	toluene,	xylene, BTX
	NCI-Yale	National Cancer	Institute-Yale	(NCI-Yale)					USA:	Connecticut					1996-2000	182	705	Population		Frequency-	matched by age				62.5 (14.0)		0	12.3			92.7	Self-reported	Exposure, open-	ended, prompted	by list including	'benzene',	'toluene',	'xylene',	'aromatic	hydrocarbons,
	Cross-Canada	Cross-Canada							Canada: Alberta,	British	Columbia,	Manitoba,	Ontario, Quebec,	Saskatchewan	1991-1994	327	1428	Population		Frequency-	matched by age,	study centre			56.1 (15.8)		100	36.1			Not collected	Self-reported	exposure,	specific question	for 'solvents'
	Italian	Multicentre	Italian	Multicentre						Italy: Firenze,	Forli, Imperia,	Latina, Ragusa,	Siena, Torino			1991-1993	258	1095	Population		Frequency-	matched by age,	sex, study centre			52.3 (13.5)		50.5	60.2			Not collected	Expert	assessment:	benzene,	toluene, xylene,	aromatic	hydrocarbons
	Population	Health	Population	Health						USA:	Georgia,	Michigan,	New Jersey			1986-1989	569	2137	Population		Frequency-	matched by	age, sex,	race, study	centre	62.2 (10.9)		60.6	40.8			56.7	None
	LACCMM	Los Angeles	County Case-	Control Study	of Multiple	Myeloma	(LACCMM)		USA: Los	Angeles County					1985-1990	274	276	Population		Pair-matched by	age, sex, race				61.1 (9.0)		54.7	20.4			68.4	Self-reported	exposure, open-	ended,	prompted by list	including	'benzene',	'toluene',	'xylene', 'other
	study label FHCRC-1980s	Study name Fred Hutchinson	Cancer Research	Center-1980s	(FHCRC-1980s)				Study centre USA: Georgia,	Michigan,	Washington State,	Utah			Years 1977-1981	N cases 681	N controls 1679	Source of Population	controls	Matching Frequency-matched	by age, sex, study	centre			Age in years 62.6 (10.0)	(mean (SD))	Male sex (%) 54.8	Education less 45.0	than high	school	graduate (%)	White race (%) 76.2	Information Self-reported	available for exposure, specific	adjustment of questions for	JEM-assigned 'benzene',	exposure 'cleaning solvents'	probability

Table 2

 2 Association of aromatic hydrocarbon solvent cumulative intensity exposure * with risk of multiple myeloma † ‡

Any exposure (quartiles of cumulative intensity) High-probability exposure (quartiles of cumulative intensity) § ¶

		Referent	0.95 (0.85 to 1.06)		0.76 (0.54 to 1.07)	1.06 (0.81 to 1.40)	1.07 (0.80 to 1.44)	1.42 (1.08 to 1.86)	P trend=0.01	Referent	0.90 (0.80 to 1.02)		0.86 (0.63 to 1.16)	0.96 (0.71 to 1.30)	1.09 (0.81 to 1.46)	1.63 (1.25 to 2.12)	P trend=0.0007	Referent	0.88 (0.78 to 1.00)		0.85 (0.63 to 1.15)	0.91 (0.66 to 1.24)	1.09 (0.81 to 1.45)	1.63 (1.25 to 2.13)	P trend=0.0006
	Cases Controls	7513 Unexposed 1921	2210 Low-probability/medium-probability exposure 637	High-probability exposure	220 Quartile 1 43	252 Quartile 2 76	231 Quartile 3 67	209 Quartile 4 88		7969 Unexposed 2063	1754 Low-probability/medium-probability exposure 493	High-probability exposure	259 Quartile 1 58	224 Quartile 2 59	228 Quartile 3 66	204 Quartile 4 92		8103 Unexposed 2107	1640 Low-probability/medium-probability exposure 456	High-probability exposure	260 Quartile 1 58	214 Quartile 2 54	231 Quartile 3 67	198 Quartile 4 90	Unexposed 1898
		Referent	-		0.91 (0.76 to 1.09)	0.94 (0.80 to 1.11)	0.94 (0.80 to 1.12)	1.16 (0.98 to 1.37)	P trend=0.10	Referent	-		0.91 (0.75 to 1.09)	0.90 (0.75 to 1.07)	0.94 (0.79 to 1.12)	1.12 (0.94 to 1.34)	P trend=0.22	Referent	-		0.88 (0.72 to 1.06)	0.87 (0.72 to 1.04)	0.96 (0.80 to 1.15)	1.12 (0.95 to 1.33)	P trend=0.22	Referent
	Cases Controls	Benzene Unexposed 1921 7513			Quartile 1 179 769	Quartile 2 232 801	Quartile 3 231 811	Quartile 4 271 743		Toluene Unexposed 2063 7969			Quartile 1 164 704	Quartile 2 189 669	Quartile 3 193 671	Quartile 4 224 628		Xylene Unexposed 2107 8103			Quartile 1 153 672	Quartile 2 178 650	Quartile 3 181 622	Quartile 4 215 602	BTX f Unexposed 1898 7391

Table 3

 3 Association of cumulative intensity * of high-probability exposure to aromatic hydrocarbon solvents with risk of multiple myeloma † ‡ §

	within lag periods

Controls Exposure occurring >20 years before diagnosis date Cases Controls Exposure within 20 years of diagnosis date

  Cumulative intensity estimated as job-specific exposure intensity multiplied by job duration, summed across all jobs. Note that a subject can be included as exposed during both lag periods, with cumulative intensity calculated separately according to the number of years worked in exposed jobs during each period. † ORs and 95% CIs from logistic regression models, with adjustment for study, study centre, age, sex, education and race.

	Referent	0.62 (0.37 to 1.02)	0.96 (0.64 to 1.45)	1.38 (0.92 to 2.05)	1.87 (1.28 to 2.73)	P trend=0.002	Referent	0.73 (0.45 to 1.17)	0.92 (0.62 to 1.39)	1.26 (0.83 to 1.89)	2.31 (1.61 to 3.31)	P trend=0.001	Referent	0.74 (0.45 to 1.19)	0.80 (0.52 to 1.26)	1.24 (0.84 to 1.84)	2.42 (1.68 to 3.48)	P trend=0.001	Referent	0.68 (0.43 to 1.06)	0.89 (0.60 to 1.32)	1.21 (0.83 to 1.77)	2.07 (1.47 to 2.92)	P trend=0.0007
	7513	122	122	99	96		7969	125	128	109	92		8103	122	116	118	86		7391	145	141	128	109
	1921	19	31	37	44		2063	21	31	33	53		2107	21	25	36	52		1898	24	33	40	57
	Referent	0.87 (0.62 to 1.21)	1.18 (0.88 to 1.58)	1.31 (0.95 to 1.81)	1.19 (0.89 to 1.59)	P trend=0.16	Referent	1.05 (0.76 to 1.45)	1.12 (0.82 to 1.53)	1.01 (0.74 to 1.37)	1.46 (1.09 to 1.96)	P trend=0.03	Referent	1.01 (0.73 to 1.40)	1.11 (0.81 to 1.51)	1.02 (0.74 to 1.39)	1.45 (1.08 to 1.94)	P trend=0.03	Referent	0.94 (0.68 to 1.30)	1.14 (0.87 to 1.50)	1.16 (0.87 to 1.55)	1.30 (0.98 to 1.72)	P trend=0.09
	7513	204	195	150	186		7969	185	186	195	169		8103	187	183	189	168		7391	201	245	203	197
	Benzene Unexposed 1921	Quartile 1 47	Quartile 2 67	Quartile 3 57	Quartile 4 72		Toluene Unexposed 2063	Quartile 1 52	Quartile 2 58	Quartile 3 58	Quartile 4 74		Xylene Unexposed 2107	Quartile 1 51	Quartile 2 57	Quartile 3 57	Quartile 4 73		BTX ¶ Unexposed 1898	Quartile 1 51	Quartile 2 80	Quartile 3 71	Quartile 4 79
																								*

Occup Environ Med. Author manuscript; available in PMC 2022August 18.

0.92 (0.82 to 1.03) Occup Environ Med. Author manuscript; available in PMC 2022 August 18.

Funding

This study was funded by the National Institute of Environmental Health Sciences (5R21ES021592).

sharing statement Data from this pooled study that comprised multiple case-control studies conducted by individual institutions may be shared only with permission of the individual institutions, which hold the original study data.

Supplementary Material

Refer to Web version on PubMed Central for supplementary material.

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