Institute for Occupational Physiology at the University of Dortmund, Leibniz Research Center for Working Environment and Human Factors, D-44139 Dortmund, Germany
Received March 14, 2004; accepted April 30, 2004
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ABSTRACT |
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Key Words: carcinogens; risk assessment; genotoxins; thresholds; standard setting.
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INTRODUCTION |
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GENOTOXIC VERSUS NONGENOTOXIC CARCINOGENS |
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Nongenotoxic carcinogens (e.g., hormones, tumor promoters, and TCDD) are characterized by a conventional dose response that allows derivation of a no-observed-adverse-effect level (NOAEL). Insertion of an uncertainty (or safety) factor permits the derivation of permissible exposure levels at which no relevant human cancer risks are anticipated. The risk assessment approach for nongenotoxic chemicals is generally similar among different regulatory bodies worldwide (Seeley et al., 2001).
For genotoxic carcinogens, Streffer et al. (2004) suggest several possibilities for assessing carcinogenic risk. Positive data of chromosomal effects only, e.g., aneugenicity or clastogenicity, in the absence of mutagenicity, may support the characterization of a compound that produces carcinogenic effects only at high, toxic doses (Schoeny, 1996
). Non-DNA-reactive genotoxicants, such as topoisomerase inhibitors (Lynch et al., 2003
) or inhibitors of the spindle apparatus or associated motor proteins (Decodier et al., 2002
), are considered in this respect. In these cases, relevant arguments have been put forward in favor of the existence of practical thresholds (Crebelli, 2000
; Parry et al., 2000
). Sometimes, a practical threshold may be quite low compared to existing environmental or occupational exposures (Thier et al., 2003
). Moreover, genotoxicity (especially when of a local nature) may be relevant only under conditions of sustained local tissue damage and associated increased cell proliferation. Formaldehyde (Morgan, 1997
) and vinyl acetate (Bogdanffy and Valentine, 2003
) have been noted as examples. Also, the derivation of practical thresholds and, thus, of health-based exposure limits may appear sufficiently justified.
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THRESHOLD TYPES FOR CARCINOGENS |
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The idea to differentiate between apparent- versus real- threshold genotoxicants dates back to Seiler (1977). Kirsch-Volders et al. (2000)
further elaborated on this issue, arriving at definitions for absolute, real or biological, apparent, and statistical thresholds. Hengstler et al. (2003)
distinguished between perfect and practical thresholds, based on different types of mechanisms. Basically, nongenotoxic carcinogens have been connected with a real (Kirsch-Volders et al., 2000
) or perfect (Hengstler et al., 2003
) threshold. A statistical threshold (Kirsch-Volders et al., 2000
) has been attributed to mitotic spindle poisons where the primary interaction occurs with protein(s) and not with DNA. Definitions of apparent (Kirsch-Volders et al., 2000
) or practical thresholds (Hengstler et al., 2003
) are based on the concept that the chemical should cause no genotoxic effect at very low or immeasurable target concentrations (Seiler, 1977
). Such apparent thresholds have been connected with rapid degradation (toxicokinetics) of the chemical or to factors in general that limit target exposures (e.g., DNA repair, apoptosis, and immune surveillance; Kirsch-Volders et al., 2000
).
Taking these concepts and denominations together, it is proposed to basically distinguish between true and practical thresholds (Bolt et al., 2004). Thus, true thresholds include perfect thresholds (as defined by Hengstler et al., 2003
) and both real and statistical thresholds (as defined by Kirsch-Volders et al., 2000
). Practical thresholds (Hengstler et al., 2003
) are regarded equivalent to apparent thresholds, as defined by Kirsch-Volders et al. (2000)
.
These different types of thresholds for carcinogens are opposed to the classical dose response of carcinogens for which no threshold can be defined. Streffer et al. (2004) suggested that a further differentiation be made within this group of genotoxicants. For many chemical carcinogens (and for ionizing radiation as well), a linear nonthreshold (LNT) extrapolation appears appropriate and scientifically well-founded. But, there is more uncertainty for other chemicals, in which cases LNT extrapolations may be used as a default procedure, backed by the precautionary principle.
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CATEGORIES OF CARCINOGENS IN VIEW OF RISK ASSESSMENT |
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DISCUSSION |
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In a previous Forum article on acrylamide in foods, Dybing and Sanner (2003) preferred a default linear extrapolation of carcinogenic risk. But, at the same time, they noted that many processes may result in nonlinearity of the dose response for acrylamide carcinogenicity in the low-dose region, including detoxication reactions, cell cycle arrest, DNA repair, apoptosis, and immune surveillance.
Similarly, the Scientific Committee on Occupational Exposure Limits (SCOEL) of the European Union, when recently reviewing acrylonitrile, acknowledged current arguments in favor of secondary mechanisms of carcinogenicity (for details, see Bolt, 2003). Nevertheless, as acrylonitrile appears from the experimental bioassays as a pluripotent (multiorgan) carcinogen and an unspecified impact of genotoxicity cannot be ruled out, it seemed prudent to SCOEL to consider in this case a nonthreshold mechanism as a default.
The issue of the nephrocarcinogenicity of trichloroethylene is presently being discussed in Germany; a compilation of relevant arguments was reported previously (Bolt, 2003). Basically, there is a genotoxic initiation at the target organ level, expressed as unique somatic mutations of the VHL tumor suppressor gene, and subsequent promotion/progression triggered by tubular nephrotoxicity (Brüning and Bolt, 2000
). In sum, it appears that human carcinogenicity of trichloroethylene is a high-dose phenomenon because the latter step is essential. New data have corroborated the existence of a secondary mechanism of trichloroethylene-induced nephrotoxicity, as a result of metabolic formic acid formation and acidosis at the target organ level upon increased excretion of formic acid (Green et al., 2003
).
These and other examples show that, on one hand, the process of introducing new ways of evaluating carcinogenic risk of chemicals is slow and cumbersome. On the other hand, substantial progress is being made in the incorporation of new mechanistic data into these regulatory procedures. Further research efforts in this field are warranted and should be encouraged and supported. This applies to industry, as far as important industrial chemicals are concerned, to academia, in light of new mechanisms of toxicity, and to grant-giving institutions. Elucidation of the mechanisms involved will also help in the critical process of risk communication (Degen, 2003).
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NOTES |
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1 To whom correspondence should be addressed at Institut für Arbeitsphysiologie an der Universität Dortmund, Leibniz Research Centre for Working Environment and Human Factors, Ardeystrasse 67, D-44139 Dortmund, Germany. Fax: +49 231-1084403. E-mail: bolt{at}ifado.de.
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