juan alguacil, md huelva university brussels, 26 june 2012 limits on occupational exposure limits...

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

Dr. Juan Alguacil Ojeda Huelva University

Comparison of Toenails and Urine as Matrices for Bio-Monitoring of Metal Levels in Exposed Workers

STUDY POPULATIONTABLE 1: Main Characteristics

Metal workers Service workers

n=56 % n=38 %

Study AreaHuelva 37 66.1% 38 100%Cadis 18 32.1% - -Seville 1 1.8% - -

SexWomen 5 8.9% 7 18.4%

AgeMean 44 48SD 10 6

RESULTS

Metals among exposed vs. unexposed workers

Urine

Exposed Higher than Unexposed Toenails

Exposed Higher than Unexposed

Al - 0.001 NOAs 0.131 NO <0,001 YESBa 0.552 YES <0,001 YESBe 0.130 NO <0,001 NOCd 0.970 YES <0,001 YESCo 0.682 YES 0.001 YESCr - <0,001 YESCu 0.556 YES <0,001 YESFe - 0.001 YESHg 0.512 YES 0.007 YESLi <0,001 YES 0.001 YES

U Mann-Whitney test for medians

RESULTS

Metals among exposed vs. unexposed workers

Urine

Exposed Higher than Unexposed Toenails

Exposed Higher than Unexposed

Mn - 0.003 YESMo 0.556 YES 0.001 YESNi - 0.189 YESPb <0,001 YES <0,001 YESSe 0.796 YES <0,001 YESSr 0.563 YES <0,001 YESTl 0.001 YES <0,001 YESU - 0.001 YESV <0,001 YES <0,001 YESW 0.454 YES <0,001 YESZn 0.620 YES 0.201 YES

U Mann-Whitney test for medians

RESULTS

rho p rho p rho p

As 0.03 0.852 0.428 0.001 0.224 0.024

Li 0.034 0.829 0.283 0.030 0.274 0.006

Pb 0.039 0.804 0.555 <0.001 0.483 <0.001

Tl -0.065 0.685 0.221 0.089 0.288 0.003

V -0.070 0.660 0.215 0.098 0.33 0.001

W 0.111 0.514 0.267 0.039 0.178 0.081

Cd 0.257 0.100 -0.017 0.898 0.066 0.511

Hg 0.284 0.069 -0.204 0.118 -0.076 0.449

n=42 n=60 n=102

Unexposedworkers

Exposedworkers

Alltogheter

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







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

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

Some Common Multiple Exposures

TASK AGENTS

Dry Cleaning Methylene Chloryde, percloroethylene, trichloroethylene, 1,1,1-trichlorethane

Painting Toluene, xilene, methylethylKetone (MEK), methylisobuthylketone (MIBK),Stoddard solvent

Graphic arts Methylene Chloryde, dichlorethane

Petrol refineries Bencene, toluene, xylene, dichloretane

Welding Welding fumes, heavy metals pesados, ozone

Agriculture Pesticides, solvents, engine exhausts

Shoe making Toluene, xilene, hexane, methylbuthylKetone (MBK), methylethylketona (MEK), heptane

Wood industry Wood dust, pesticides, solvents


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

http://www.irsst.qc.ca/en/_outil_100037.html

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

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)







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


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?


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

juan alguacil, md huelva university brussels, 26 june 2012 limits on occupational exposure limits...

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