Juan Alguacil, MD Huelva University Brussels, 26 June 2012 Limits on Occupational Exposure Limits...
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Transcript of 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
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
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
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
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
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
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
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