Juan Alguacil, MD Huelva University Brussels, 26 June 2012 Limits on Occupational Exposure Limits for Carcinogens 8th Seminar on workers’ protection & chemicals Threshold vs. Non Threshold Carcinogens

OUTLINE Cancer is a chronic disease where cumulated long term exposure is relevant, and 8-hour thresholds do not account for chronic exposure Update of the documental basis can be improved Most thresholds are not based on studies in humans (epidemiological or toxicological) Thresholds, concomitant exposures and mixtures Chemicals with multiple mechanisms of action Validity of inferences for low-dose effects and accuracy of NOAELs

OUTLINE Cancer is a chronic disease where cumulated long term exposure is relevant, and 8-hour thresholds do not account for chronic exposure Update of the documental basis can be improved Most thresholds are not based on studies in humans (epidemiological or toxicological) Thresholds, concomitant exposures and mixtures Chemicals with multiple mechanisms of action Validity of inferences for low-dose effects and accuracy of NOAELs

Dr. Juan Alguacil Ojeda Huelva University Comparison of Toenails and Urine as Matrices for Bio-Monitoring of Metal Levels in Exposed Workers

STUDY POPULATION TABLE 1: Main Characteristics

RESULTS

CONCLUSION Multielemental analysis of toenail samples properly captures occupational exposure to metals, and might be useful when long term bio- monitoring be of interest

CUMULATIVE EXPOSURE 8-hours based exposure limits account for the acute effect of a dose that takes into account a correction factor for a life-long term occupational exposure, but do not account for the chronic (continuous) effect of the cumulative exposure Noise is a good example (though not carcinogenic) Need for studies based in humans (e.g. cohorts of workers, environmentally exposed populations) to assess the risk of cumulative exposure Known carcinogenic agents increasing the risk at chronic environmental exposure are candidates to follow

OUTLINE Cancer is a chronic disease where cumulated long term exposure is relevant, and 8-hour thresholds do not account for chronic exposure Update of the documental basis can be improved Most thresholds are not based on studies in humans (epidemiological or toxicological) Thresholds, concomitant exposures and mixtures Chemicals with multiple mechanisms of action Validity of inferences for low doses effects and accuracy of NOAELs

Update for the documental basis can be improved No need to re-invent the wheel but … Need to update scientific toxicological information that gives support to TLVs when necessary Take into account new assays/methods and not only the classical ones Scarce epidemiological and toxicological studies in humans

OUTLINE Cancer is a chronic disease where cumulated long term exposure is relevant, and 8-hour thresholds do not account for chronic exposure Update of the documental basis can be improved Most thresholds are not based on studies in humans (epidemiological or toxicological) Thresholds, concomitant exposures and mixtures Chemicals with multiple mechanisms of action Validity of inferences for low doses effects and accuracy of NOAELs

Thresholds not based on studies in humans The most comprehensive analysis of genotoxicity and carcinogenesis data showed that the genotoxicity testing battery is highly sensitive for detection of carcinogens, detecting 93% of carcinogens However, the testing paradigm features low specificity (Kirkland et al.,2005, 2006) 50% of the noncarcinogens among marketed pharmaceuticals had some positive genotoxicity findings (Snyder and Green, 2001) The discrepancy is due to limitations of genotoxicity endpoints and assays, such as insufficiency of certain in vitro assays to model the in vivo target organ situation and the complexity of carcinogenic mechanisms

Thresholds not based on studies in humans In case of carcinogenicity studies, the analysis of several databases showed that 50% of compounds tested positive in at least one species or sex (Hoffmann and Hartung, 2006; MacDonald, 2004) This high incidence and other research questioned the human relevance for of tumors induced in rodents (Knight et al., 2006;Ward, 2007) Arsenic would be an example of the lack of sensitivity of animal models to identify human carcinogens

Thresholds not based on studies in humans Scientifically, it may be more appropriate to identify key mechanisms involved in human carcinogenesis as a means to identify the agents that can play a role in advancing these mechanisms—rather than starting with an animal tumor and evaluating whether each event is similar or different in humans

OUTLINE Cancer is a chronic disease where cumulated long term exposure is relevant, and 8-hour thresholds do not account for chronic exposure Update of the documental basis can be improved Most thresholds are not based on studies in humans (epidemiological or toxicological) Thresholds, concomitant exposures and mixtures Chemicals with multiple mechanisms of action Validity of inferences for low doses effects and accuracy of NOAELs

Some Common Multiple Exposures

Thresholds, concomitant exposures and mixtures Several agents can affect the same organ Within a mixture, usually, the risk assessment is based on the agent more toxic in the mixture (Kortekamp A. 2008)  No problems when there is only one toxic agent in the mixture  or when the total toxicity of the mixture is higher than the toxicity of such agent

Thresholds, concomitant exposures and mixtures ACGIH, and Directive (98/24/EC) recommend assuming additive effects when substances affect the same organ, unless there is evidence for non-additive effects The effect of concomitant exposures can be additive… or not...  Arsenic and cadmium potentiate their effects on kidney toxicity  The effect can be antagonistic (e.g. for some xenoestrogens (Rajapakse et al 2004)) Some xenoestrogens can interact at levels below their NOAEL (Silva et al 2002)

Concomitant exposures and mixtures “Mixie” Database developed by the Canadian Institute Robert-Sauvé   Data for about 700 agents  Identifies when two agents can affect the same organ and provides information on whether there are studies on the interaction between both agents

OUTLINE Cancer is a chronic disease where cumulated long term exposure is relevant, and 8-hour thresholds do not account for chronic exposure Update of the documental basis can be improved Most thresholds are not based on studies in humans (epidemiological or toxicological) Thresholds, concomitant exposures and mixtures Chemicals with multiple mechanisms of action Validity of inferences for low doses effects and accuracy of NOAELs

Multiple mechanisms of action

Multiple mechanisms There are no routine screening tests for mechanisms other than genotoxicity, including the epigenetic effects that can also play a critical role in induction and progression of human cancer Available genotoxicity tests do not readily accommodate the concept that a single chemical may have multiple impacts on the carcinogenic process

Multiple mechanisms The analysis of 8 selected Group I carcinogens considered whether chemical carcinogens may act through multiple mechanisms and found that simple dichotomous characterization regarding whether a chemical is ‘‘genotoxic’’ or ‘‘non- genotoxic,’’ though often part of risk assessment approaches, is not particularly informative

Multiple mechanisms IARC recently modified its guidelines to allow an agent to be classified as possibly carcinogenic to humans (Group 2B) ‘‘solely on the basis of strong evidence from mechanistic and other relevant data’’ (Before this change, a classification in Group 2B required at least limited evidence of carcinogenicity in experimental animals)

OUTLINE Cancer is a chronic disease where cumulated long term exposure is relevant, and 8-hour thresholds do not account for chronic exposure Update of the documental basis can be improved Most thresholds are not based on studies in humans (epidemiological or toxicological) Thresholds, concomitant exposures and mixtures Chemicals with multiple mechanisms of action Validity of inferences for low-dose effects and accuracy of NOAELs

Dose Response and NOAEL Available mechanistic data typically come from high dose experiments that have rarely been conducted in the context of or under conditions that are comparable to animal bioassays or epidemiologic studies in which increased cancer risk was observed Thus, reaching conclusions about the mode of action of a chemical at low doses is almost always difficult and controversial

Dose Response and NOAEL A good modeling of the dose-response relationship can provide useful information on the mechanism/s of action The dose-response relationship for genotoxic carcinogenic agents is based on animal data, and the inference to humans implies some limitations (assumptions on toxicokinetics, toxicodynamics, metabolism, mechanism of actions, influence of non genotoxic mechanism, and susceptible populations) The NOAEL approach does not provide empirical information on biological processes below the NOAEL, increasing uncertainty on the magnitude of variability below such level Will DNELs susbtitute NOAELs?

Dose Response and NOAEL Lucier et al. stated that the dose–response curve would in fact be linear in the low-dose region because the ‘‘occupancy of one receptor would produce a response, although it is unlikely that this response could be detected’’ experimentally Human variability and background exposure tend to broaden and increase the linearity of the dose–response curve “Each modulating factor divides the population up into subpopulations of different susceptibility so that nonlinearities that could be present in a homogeneous population are flattened out. A linear extrapolation of a human cancer risk to low dose might therefore be appropriate under certain conditions even if the dose–response curve in animals has a strongly sigmoidal (non-linear) shape” (Lutz 1999)

Dose Response and NOAEL The concept that mechanisms inform the shape of the dose– response curve at low doses has been challenged by several experimental studies including the recent demonstrations that the dose–response curves for assays for gene mutations show a non-linear or apparent threshold response for some (MMS and EMS) but not all (MNU or ENU) mutagens (Doak et al 2007) On the other hand, no threshold has been demonstrated for diverse effects including non-genotoxic effects, such as receptor binding and clastogenesis (chromosome breakage leading to micronucleus formation) from mitomycin C and diepoxybutane (Grawe et al 1998) DNA adduct formation following exposure to benzene and other chemicals in rodents also lacks an apparent threshold