Human Carcinogenic Risk Evaluation, Part II: Contributions of the EUROTOX Specialty Section for Carcinogenesis

Hermann M. Bolt1 and Gisela H. Degen

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


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 GENOTOXIC VERSUS NONGENOTOXIC...
 THRESHOLD TYPES FOR CARCINOGENS
 CATEGORIES OF CARCINOGENS IN...
 DISCUSSION
 REFERENCES
 
There is growing recognition that carcinogenic risk extrapolation to low doses (and standard setting) should consider the mode of action of a given chemical. So far, there is agreement on distinguishing between genotoxic and nongenotoxic chemicals; yet, further differentiations seem appropriate. For genotoxic carcinogens, case studies of chemicals point to many possibilities for assessing carcinogenic risk. There are numerous, apparently genotoxic carcinogens where practical thresholds are a matter of discussion. For instance, positive data of chromosomal effects only, in the absence of mutagenicity, may support the characterization of a compound that produces carcinogenic effects only at high, toxic doses. There is a wide consensus that for non-DNA-reactive genotoxicants, such as aneugens, thresholds should be defined. Specific mechanisms of clastogenicity have been repeatedly addressed as also having thresholds, such as topoisomerase II poisons, or mechanisms based on reactive oxygen. These and other arguments together lead to the distinction of four groups of carcinogens, which have been introduced (C. Streffer et al., 2004Go, Springer-Verlag). There are nonthreshold genotoxic carcinogens (for low-dose risk assessment, the linear nonthreshold [LNT] model appears appropriate); genotoxic carcinogens, for which the existence of a threshold cannot be sufficiently supported (in these cases the LNT model is used as a default assumption, based on the scientific uncertainty and backed by the precautionary principle); genotoxic carcinogens for which a practical threshold is supported; and nongenotoxic carcinogens and non-DNA-reactive carcinogens (for these compounds a true [perfect] threshold is associated with a clearly founded no-observed-adverse-effect level).

Key Words: carcinogens; risk assessment; genotoxins; thresholds; standard setting.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 GENOTOXIC VERSUS NONGENOTOXIC...
 THRESHOLD TYPES FOR CARCINOGENS
 CATEGORIES OF CARCINOGENS IN...
 DISCUSSION
 REFERENCES
 
Worldwide developments on how to assess carcinogenicity of chemicals (Seeley et al., 2001Go) are paralleled by continuing scientific discussions in Europe. Specifically, in September 1998, a joint symposium on "Dose-Response and Threshold-Mediated Mechanisms in Mutagenesis" was convened in Salzburg, Austria, by the European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC) and the European Environmental Mutagen Society (EEMS) to discuss new concepts of thresholds in mutagenesis and carcinogenesis (Sarrif et al., 2000Go). Within the EUROTOX 2002 congress (Budapest, September 2002), the issue of possible thresholds in genotoxicity was taken up by the EUROTOX Specialty Section Carcinogenesis (Bolt, 2003Go; Kirsch-Volders et al., 2003Go; Pratt and Barron, 2003Go; Thier et al., 2003Go). The discussion of new aspects in carcinogenicity categorization of chemicals was resumed in October 2003 at the Fifth International Congress of the Turkish Society of Toxicology in Antalya, Turkey. In parallel, the European Academy for Research on Consequences of Scientific and Technical Developments, Bad Neuenahr-Ahrweiler, has convened a working group on "Dose-Effect Relations in the Low-Dose Range and Risk Evaluation" (Streffer et al., 2004Go). The resulting new perspectives have been summarized for the Festschrift in honor of the late EUROTOX officer Christian Hodel (Bolt et al., 2004Go). This Forum is based on that summary.


    GENOTOXIC VERSUS NONGENOTOXIC CARCINOGENS
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 ABSTRACT
 INTRODUCTION
 GENOTOXIC VERSUS NONGENOTOXIC...
 THRESHOLD TYPES FOR CARCINOGENS
 CATEGORIES OF CARCINOGENS IN...
 DISCUSSION
 REFERENCES
 
There is almost general agreement that distinction between genotoxic and nongenotoxic compounds should be made when conducting assessments of cancer risk to humans.

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., 2001Go).

For genotoxic carcinogens, Streffer et al. (2004)Go 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, 1996Go). Non-DNA-reactive genotoxicants, such as topoisomerase inhibitors (Lynch et al., 2003Go) or inhibitors of the spindle apparatus or associated motor proteins (Decodier et al., 2002Go), are considered in this respect. In these cases, relevant arguments have been put forward in favor of the existence of practical thresholds (Crebelli, 2000Go; Parry et al., 2000Go). Sometimes, a practical threshold may be quite low compared to existing environmental or occupational exposures (Thier et al., 2003Go). 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, 1997Go) and vinyl acetate (Bogdanffy and Valentine, 2003Go) have been noted as examples. Also, the derivation of practical thresholds and, thus, of health-based exposure limits may appear sufficiently justified.


    THRESHOLD TYPES FOR CARCINOGENS
 TOP
 ABSTRACT
 INTRODUCTION
 GENOTOXIC VERSUS NONGENOTOXIC...
 THRESHOLD TYPES FOR CARCINOGENS
 CATEGORIES OF CARCINOGENS IN...
 DISCUSSION
 REFERENCES
 
The assumption of a linear dose–carcinogenicity response without threshold is supported in a plausible way for numerous classical carcinogens (Hengstler et al., 2003Go). Other carcinogens may behave differently, but the precise nature of the dose response, at low doses, has not been sufficiently established. Also, differences may occur for the same compound between different tissues. In such cases, precautionary considerations will mostly lead to application of the conservative approach of a linear, low-dose extrapolation.

The idea to differentiate between apparent- versus real- threshold genotoxicants dates back to Seiler (1977)Go. Kirsch-Volders et al. (2000)Go further elaborated on this issue, arriving at definitions for absolute, real or biological, apparent, and statistical thresholds. Hengstler et al. (2003)Go 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., 2000Go) or perfect (Hengstler et al., 2003Go) threshold. A statistical threshold (Kirsch-Volders et al., 2000Go) 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., 2000Go) or practical thresholds (Hengstler et al., 2003Go) are based on the concept that the chemical should cause no genotoxic effect at very low or immeasurable target concentrations (Seiler, 1977Go). 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., 2000Go).

Taking these concepts and denominations together, it is proposed to basically distinguish between true and practical thresholds (Bolt et al., 2004Go). Thus, true thresholds include perfect thresholds (as defined by Hengstler et al., 2003Go) and both real and statistical thresholds (as defined by Kirsch-Volders et al., 2000Go). Practical thresholds (Hengstler et al., 2003Go) are regarded equivalent to apparent thresholds, as defined by Kirsch-Volders et al. (2000)Go.

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)Go 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.


    CATEGORIES OF CARCINOGENS IN VIEW OF RISK ASSESSMENT
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 INTRODUCTION
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 THRESHOLD TYPES FOR CARCINOGENS
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 DISCUSSION
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These ideas have been taken together and a practical distinction of carcinogens has been proposed, with the following examples (Streffer et al., 2004Go, as summarized by Bolt et al., 2004Go see Fig. 1):

  1. Nonthreshold genotoxic carcinogens; for risk low-dose assessment, the LNT model appears appropriate. Regulations may be based on the principle of as low as reasonably achievable (ALARA), technical feasibility, and other sociopolitical considerations. Examples include ionizing radiation, vinyl chloride, and diethylnitrosamine (Bolt et al., 2004Go).
  2. Genotoxic carcinogens, for which the existence of a threshold cannot be sufficiently supported. In these cases, the LNT model is used as a default assumption, based on the scientific uncertainty and generally backed by the precautionary principle. Examples include acrylamide (Dybing and Sanner, 2003Go), acrylo- nitrile, and arsenic.
  3. Genotoxic carcinogens for which a practical threshold is supported by studies on mechanisms and/or toxicokinetics; health-based exposure limits may be based on an established NOAEL. Examples include formaldehyde (Morgan, 1997Go) and vinyl acetate (Hengstler et al., 2003Go).
  4. Nongenotoxic carcinogens and non-DNA-reactive carcinogens; for these compounds a true (or perfect, according to Hengstler et al., 2003Go) threshold is associated with a NOAEL, and health-based exposure limits are to be derived. Examples include tumor promoters, spindle poisons, topoisomerase II poisons, and hormones.



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FIG. 1. Proposal to distinguish among groups of carcinogens (A–D) for the purposes of risk assessment and standard setting (Bolt et al., 2004Go modified).

 

    DISCUSSION
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 ABSTRACT
 INTRODUCTION
 GENOTOXIC VERSUS NONGENOTOXIC...
 THRESHOLD TYPES FOR CARCINOGENS
 CATEGORIES OF CARCINOGENS IN...
 DISCUSSION
 REFERENCES
 
The following critical points relate to the four carcinogen categories that have been described (Fig. 1):
  1. The differentiation between genotoxic and nongenotoxic is widely accepted.
  2. We have mentioned briefly the problems in considering mechanisms of genotoxicity at the chromosomal level. A more detailed treatment of this subject has been provided elsewhere (Bolt et al., 2004Go).
  3. The differentiation of weak genotoxicants with secondary mechanisms of carcinogenesis can be very difficult. Reference can be made to the discussions of formaldehyde (Morgan, 1997Go) and vinyl acetate (Bogdanffy and Valentine, 2003Go; Hengstler et al., 2003Go).
  4. Presently, numerous other important industrial chemicals, including acrylamide, acrylonitrile, and trichloroethylene, are being addressed as to the implication of practical thresholds of carcinogenicity.

In a previous Forum article on acrylamide in foods, Dybing and Sanner (2003)Go 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, 2003Go). 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, 2003Go). 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, 2000Go). 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., 2003Go).

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, 2003Go).


    NOTES
 

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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 DISCUSSION
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