Changes in the classification of carcinogenic chemicals in the work area. Section III of the German List of MAK and BAT Values

Carcinogenic chemicals in the work area are currently classified into three categories in section III of the German List of MAK and BAT Values (list of values on maximum workplace concentrations and biological tolerance for occupational exposures). This classification is based on qualitative criteria and reflects essentially the weight of evidence available for judging the carcinogenic potential of the chemicals. It is proposed that these categories - IIIA1, IIIA2, IIIB - be retained as Categories 1, 2, and 3, to correspond with European Union regulations. On the basis of our advancing knowledge of reaction mechanisms and the potency of carcinogens, these three categories are supplemented with two additional categories. The essential feature of substances classified in the new categories is that exposure to these chemicals does not contribute significantly to risk of cancer to man, provided that an appropriate exposure limit (MAK value) is observed. Chemicals known to act typically by nongenotoxic mechanisms and for which information is available that allows evaluation of the effects of low-dose exposures, are classified in Category 4. Genotoxic chemicals for which low carcinogenic potency can be expected on the basis of dose-response relationships and toxicokinetics, and for which risk at low doses can be assessed are classified in Category 5. The basis for a better differentiation of carcinogens is discussed, the new categories are defined, and possible criteria for classification are described. Examples for Category 4 (1,4-dioxane) and Category 5 (styrene) are presented.     

Carcinogens in food: priorities for regulatory action

A pragmatic possible approach to the prioritization of chemical carcinogens occurring as food contaminants is described, based on the carcinogenic risk to the population. This should be of value in ensuring that resources for assessment and management of carcinogens in food are directed to the most important areas with regard to carcinogenic risk to the population. Key components of this approach are an assessment of the carcinogenic hazard to humans combined with estimations of intakes per person and of the proportion of the population exposed. These are used to derive an index referred to as the Population Carcinogenic Index. Concerning the hazard assessment expert judgement is used to place the chemical in one of five categories. The highest category is for chemical carcinogens that are believed to act by a genotoxic mechanism. It is recognised that such compounds may vary enormously with respect to their potency and various approaches to ranking carcinogens on the basis of potency are reviewed. The approach adopted is to subdivide the genotoxic carcinogens category into high, medium and low potency based on the TD50 value. Methods of estimating intakes and exposed populations are considered and an approach which groups these into broad categories is developed. The hazard and exposure assessments are then combined to derive the Population Carcinogenicity Index.     

What do animal cancer tests tell us about human cancer risk?: Overview of analyses of the carcinogenic potency database

Many important issues in carcinogenesis can be addressed using our Carcinogenic Potency Database, which analyzes and standardizes the literature of chronic carcinogenicity tests in laboratory animals. This review is an update and overview of our analyses during the past 15 years, using the current database that includes results of 5152 experiments on 1298 chemicals. We address the following: 1. More than half the 1298 chemicals tested in long-term experiments have been evaluated as carcinogens. We describe this positivity rate for several subsets of the data (including naturally occurring and synthetic chemicals), and we hypothesize and important role in the interpretation of results for increased cell division due to administration of high doses. 2. Methodological issues in the interpretation of animal cancer tests: constraints on the estimation of carcinogenic potency and validity problems associated with using the limited data from bioassays to estimate human risk, reproducibility of results in carcinogenesis bioassays, comparison of lifetable and summary methods of analysis, and summarizing carcinogenic potency when multiple experiments on a chemical are positive. 3. Positivity is compared in bioassays for two closely related species, rats and mice, tested under similar experimental conditions. We assess what information such a comparison can provide about interspecies extrapolation. 4. Rodent carcinogens induce tumors in 35 different target organs. We describe the frequency of chemicals that induce tumors in rats or mice at each target site, and we compare target sites of mutagenic and nonmutagenic rodent carcinogens. 5. A broad perspective on evaluation of possible cancer hazards from rodent carcinogens is given, by ranking 74 human exposures (natural and synthetic) on the HERP indes.     

Strategies for evaluating carcinogenic substances

Cancer from exposure to chemicals is known for more than two centuries. Today, approximately 40 compounds have been identified as unequivocally carcinogenic in humans, more than 300 have been shown to be carcinogenic in animal experimentation. Accordingly, an old system subdivides carcinogens as human carcinogens (A1), animal carcinogens (A2, and compounds being suspective of exerting carcinogenic activity. There exist no threshoulds of effect for notorious carcinogens. In order to improve the protection of those exposed to carcinogens in the working area, a special type of tolerance values has been introduced (technical guidance values, TRK). Contrary to MAK-values, these TRKs take into account a certain residual cancer risk which in most cases can not be quantified. The amount of acceptable residual risks is a matter of political consensus which has to be organized between the societal groups involved. For the purpose of quantitative comparisons, "unit risks" have been introduced; the problematics of this category is discussed to some extend.     

Prediction of carcinogenicity from two versus four sex-species groups in the carcinogenic potency database

Prediction of a positive result in rodent carcinogenesis bioassays using two instead of four sex-species groups is examined for the subset of chemicals in the Carcinogenic Potency Database that have been tested in four sex-species groups and are positive in at least one (n = 212). Under the conditions of these bioassays, a very high proportion of rodent carcinogens that are identified as positive by tests in four groups is also identified by results from one sex of each species (86-92%). Additionally, chemicals that are classified as "two-species carcinogens" or "multiple-site carcinogens" on the basis of results from four sex-species groups are also identified as two-species or multiple-site carcinogens on the basis of two sex-species groups. Carcinogenic potency (TD50) values for the most potent target site are similar when based on results from two compared to four sex-species groups. Eighty-five percent of the potency values are within a factor of 2 of those obtained from tests in 4 sex-species groups, 94% are within a factor of 4, and 98% are within a factor of 10. This result is expected because carcinogenic potency values are constrained to a narrow range about the maximum dose tested in a bioassay, and the maximum doses administered to rats and mice are highly correlated and similar in dose level. Information that can be known in advance of a 2-yr bioassay (mutagenicity, class, route, and maximum dose to test) does not identify groups of rodent carcinogens for which four sex-species groups are required to identify carcinogenicity. The range of accurate prediction of carcinogenicity using only male rats and female mice is 93% among mutagens and 88% among nonmutagens; for various routes of administration, 88-100%; for various chemical classes, 75-100%; and for various levels of the maximum dose tested, 81-100%. Results are similar for the pair male rats and male mice. Using a strength of evidence approach, weaker carcinogens are somewhat less likely than stronger carcinogens to be identified by two sex-species groups. Strength of evidence is measured using the proportion of experiments on a chemical that are positive, the extent to which tumors occur in animals that die before terminal sacrifice, and whether the chemical induces tumors at more than one site and in more than one species.     

The genotype of the human cancer cell: implications for risk analysis

An extremely large database describes genotypes associated with the human cancer phenotype and genotypes of human populations with genetic predisposition to cancer. Aspects of this database are examined from the perspective of risk analysis, and the following conclusions and hypotheses are proposed: (1) The genotypes of human cancer cells are characterized by multiple mutated genes. Each type of cancer is characterized by a set of mutated genes, a subset from a total of more than 80 genes, that varies between tissue types and between different tumors from the same tissue. No single cancer-associated gene nor carcinogenic pathway appears suitable as an overall indicator whose induction serves as a quantitative marker for risk analysis. (2) Genetic defects that predispose human populations to cancer are numerous and diverse, and provide a model for associating cancer rates with induced genetic changes. As these syndromes contribute significantly to the overall cancer rate, risk analysis should include an estimation of the effect of putative carcinogens on individuals with genetic predisposition. (3) Gene activation and inactivation events are observed in the cancer genotype at different frequencies, and the potency of carcinogens to induce these events varies significantly. There is a paradox between the observed frequency for induction of single mutational events in test systems and the frequency of multiple events in a single cancer cell, suggesting events are not independent. Quantitative prediction of cancer risk will depend on identifying rate-limiting events in carcinogenesis. Hyperproliferation and hypermutation may be such events. (4) Four sets of data suggest that hypermutation may be an important carcinogenic process. Current mechanisms of risk analysis do not properly evaluate the potency of putative carcinogens to induce the hypermutable state or to increase mutation in hypermutable cells. (5) High-dose exposure to carcinogens in model systems changes patterns of gene expression and may induce protective effects through delay in cell progression and other processes that affect mutagenesis and toxicity. Paradigms in risk analysis that require extrapolation over wide ranges of exposure levels may be flawed mechanistically and may underestimate carcinogenic effects of test agents at environmental levels. Characteristics of the human cancer genotype suggest that approaches to risk analysis must be broadened to consider the multiplicity of carcinogenic pathways and the relative roles of hyperproliferation and hypermutation. Further, estimation of risk to general human populations must consider effects on hypersusceptible individuals. The extrapolation of effects over wide exposure levels is an imprecise process.     

Current Perspectives on Occupational Cancer Risks

On the basis of the International Agency for Research on Cancer's evaluations of occupational exposures, 22 occupational agents are classified as human carcinogens and an additional 22 agents as probable human carcinogens. In addition, evidence of increased risk of cancer was associated with particular industries and occupations, although no specific agents could be identified as etiologic factors. The main problem in the construction and interpretation of such lists is the lack of detailed qualitative and quantitative knowledge about exposures to known or suspected carcinogens. The recent examples of recognized occupational carcinogens, such as cadmium, beryllium, and ethylene oxide, stress the importance of the refinement in the methods for exposure assessment and for statistical analysis on the one hand and the potential benefits from the application of biomarkers of exposure and early effect on the other hand. Other trends that may be identified include the increasing practice of multicentric studies and investigations of exposures relevant to white collar workers and women. Finally, there is a need for investigation of occupational cancer risks in developing countries.     

Janus carcinogens and mutagens

Janus carcinogens are carcinogenic agents that, under differing conditions of cell type or dose, can instead act as anticarcinogens. Studies by Haseman and Johnson [J.K. Haseman, F.M. Johnson, Analysis of rodent NTP bioassay data for anticarcinogenic effects, Mutat. Res. , 350 (1996) 131-142], have demonstrated that many chemicals that are carcinogenic for one tissue type can have anticarcinogenic action on another tissue type. As Magni et al. [G.E. Magni, R.C. von Borstel, S. Sora, Mutagenic action during meiosis and antimutagenic action during mitosis by 5-aminoacridine in yeast, Mutat. Res., 1 (1964) 227-230] have shown in 1964, this principle holds true for chemical mutagens as well, that is 9-aminoacridine is an antimutagen in the vegetative cell and a mutagen in the sporulating cell. The conclusion can be drawn that two established carcinogens, tobacco and ionizing radiation, are indeed Janus carcinogens. In their review of 'ambiguous carcinogens' (their name), Weinberg and Storer [A.M. Weinberg, J.B. Storer, Ambiguous carcinogens and their regulation, Risk Anal., 5 (1985) 151-156], pointed out that tobacco can be classified as an ambiguous carcinogen. The strong carcinogenicity and anticarcinogenicity of tobacco smoke and/or tobacco itself (i.e., chewing tobacco) may be due to components in the mixture, not that of a single carcinogenic chemical that also may be anticarcinogenic. Kondo [S. Kondo, Health Effects of Low-Level Radiation, Kinki Univ. Press, Osaka, Japan and Medical Physics Publishing, Madison, WI, 1995, 213 pp.] has compiled data that demonstrate that human populations who survive exposures to ionizing radiation generally live longer and have less cancer than unirradiated human populations, and this Janus phenomenon goes beyond the more trivial concept of increased sensitivity to radiation of rapidly dividing tumor cells. Thiabendazole is an interesting compound in that it is both aneugenic and antimutagenic, and yet it does not appear to be a carcinogen or a mutagen. It is discussed here because aneugenesis and antimutagenesis are at extremes of the mutagenic spectrum. In general, mutagenic or carcinogenic actions usually are at least partially understood at a molecular level, whereas antimutagenic and anticarcinogenic actions usually are not. It is possible there may be numerous specific mechanisms underlying the Janus activity of different chemicals.     

The causes and prevention of cancer: the role of environment

The idea that synthetic chemicals such as DDT are major contributors to human cancer has been inspired, in part, by Rachel Carson's passionate book, Silent Spring. This chapter discusses evidence showing why this is not true. We also review research on the causes of cancer, and show why much cancer is preventable. Epidemiological evidence indicates several factors likely to have a major effect on reducing rates of cancer: reduction of smoking, increased consumption of fruits and vegetables, and control of infections. Other factors are avoidance of intense sun exposure, increases in physical activity, and reduction of alcohol consumption and possibly red meat. Already, risks of many forms of cancer can be reduced and the potential for further reductions is great. If lung cancer (which is primarily due to smoking) is excluded, cancer death rates are decreasing in the United States for all other cancers combined. Pollution appears to account for less than 1% of human cancer; yet public concern and resource allocation for chemical pollution are very high, in good part because of the use of animal cancer tests in cancer risk assessment. Animal cancer tests, which are done at the maximum tolerated dose (MTD), are being misinterpreted to mean that low doses of synthetic chemicals and industrial pollutants are relevant to human cancer. About half of the chemicals tested, whether synthetic or natural, are carcinogenic to rodents at these high doses. A plausible explanation for the high frequency of positive results is that testing at the MTD frequently can cause chronic cell killing and consequent cell replacement, a risk factor for cancer that can be limited to high doses. Ignoring this greatly exaggerates risks. Scientists must determine mechanisms of carcinogenesis for each substance and revise acceptable dose levels as understanding advances. The vast bulk of chemicals ingested by humans is natural. For example, 99.99% of the pesticides we eat are naturally present in plants to ward off insects and other predators. Half of these natural pesticides tested at the MTD are rodent carcinogens. Reducing exposure to the 0.01% that are synthetic will not reduce cancer rates. On the contrary, although fruits and vegetables contain a wide variety of naturally-occurring chemicals that are rodent carcinogens, inadequate consumption of fruits and vegetables doubles the human cancer risk for most types of cancer. Making them more expensive by reducing synthetic pesticide use will increase cancer. Humans also ingest large numbers of natural chemicals from cooking food. Over a thousand chemicals have been reported in roasted coffee: more than half of those tested (19/28) are rodent carcinogens. There are more rodent carcinogens in a single cup of coffee than potentially carcinogenic pesticide residues in the average American diet in a year, and there are still a thousand chemicals left to test in roasted coffee. This does not mean that coffee is dangerous but rather that animal cancer tests and worst-case risk assessment, build in enormous safety factors and should not be considered true risks. The reason humans can eat the tremendous variety of natural chemical "rodent carcinogens" is that humans, like other animals, are extremely well protected by many general defense enzymes, most of which are inducible (i.e., whenever a defense enzyme is in use, more of it is made). Since the defense enzymes are equally effective against natural and synthetic chemicals one does not expect, nor does one find, a general difference between synthetic and natural chemicals in ability to cause cancer in high-dose rodent tests. The idea that there is an epidemic of human cancer caused by synthetic industrial chemicals is false. In addition, there is a steady rise in life expectancy in the developed countries. Linear extrapolation from the maximum tolerated dose in rodents to low level exposure in humans has led to grossly exaggerated mortality forecasts. Such extrapo     

Effect of size, shape and hardness of particles in suspension on oral texture and palatability

Trans-species, multiple site (particularly common site between species), mutagenic rodent carcinogens are less affected by the influences of polymorphic genes than are chemicals inducing more limited carcinogenic effects. Trans-species carcinogens, therefore, should represent a first priority for attention for human health risk.     

Estimate of mortality from occupational cancer and of carcinogen exposure in the workplace in Spain in the 90's

We estimated the number of cancers attributed to occupational exposures in Spain, and examined the prevalence of carcinogenic exposures in the workplace. We used population, labour, mortality and morbidity statistics and applied an approach used by Doll and Peto for the population of the USA. In men 6% and in women 1% of all cancers can be attributed to occupational exposures. Lung cancer accounts for 62% of all occupational cancers. About 402,346 men and women are employed in industries or occupations entailing a well recognised carcinogenic risk. In addition, a large but unquantifiable number of workers are employed in various other occupations and industries where exposure to carcinogenic chemical or physical agents may occur. The identification and control of carcinogenic exposures may lead to the prevention of a considerable number of cancers in the Spanish adult population.     

Risk assessment of carcinogens in food with special consideration of non-genotoxic carcinogens. Scientific arguments for use of risk assessment and for changing the Delaney Clause specifically

The document "Risk Assessment of Carcinogens in Food with Special Consideration of Non-Genotoxic Carcinogens" was produced by the International Federation of Societies of Toxicologic Pathologists on the occasion of its triannual meeting in Tours, France, April 23-26, 1995. Subsequently, it was endorsed by the North American Society of Toxicologic Pathologists at its annual meeting in San Diego, CA, USA, June 11-15, 1995. This document was written to address up-to-date risk assessment of carcinogens and anachronisms in the Delaney Clause of the US Federal Food, Drug and Cosmetic Act which have become evident since its enactment in 1958. In the intervening years, major progress has been made in understanding mechanisms of cancer induction and in recognizing causes of human cancer. The Clause in conjunction with its present legal interpretation and implementation does not provide for rational, scientific evaluation of carcinogens. It ignores the fact that the diverse mechanisms now known to underlie cancer increases in rodents exposed to high doses of chemicals are often inapplicable to man. In this regard, current evaluation of chemicals based on the tenets of the Delaney Clause is irrational in many cases. The document presents several examples of chemicals to which humans may be exposed through food and which illustrate the need for science-based risk assessment. Appropriate risk assessment methods are available to provide assurance of negligible risk, and accordingly, it is recommended that the Delaney Clause be rescinded as it has outlived its usefulness. This will enable US governmental agencies to regulate the use of chemicals in foods by using appropriate current scientific methods on a case by case basis within the context of other relevant legislation.     

Transplacental and transgenerational carcinogenesis

Effects of exposure to carcinogens at early stages of ontogenesis are considered. An increased cancer risk due to prenatal exposure may be related to: 1) exposure of the fetus during pregnancy to chemicals able to cross the placental barrier or to radiation; 2) exposure to a chemical or radiation of the parents or one parent prior to conception. In transplacental carcinogenesis, the effects observed after birth are a consequence of a direct interaction of the carcinogen with somatic cells of the fetus. DES and radiation were shown to increase cancer risk in humans following exposure during pregnancy, while in experimental animals a large variety of chemicals of quite different structure (including the widely used therapeutic agent cisplatin) were demonstrated to induce tumors in the progeny after administration during pregnancy. The experimental multigeneration effect of carcinogens is manifested in an increased incidence of tumors in several generations of untreated descendants of: a) females exposed to carcinogen during pregnancy; b) males exposed to carcinogen prior to mating with untreated females. The inherited change may be an initiating event revealed by the exposure during post-natal life to a promoting agent. In humans deleterious information inherited through the germ cells (occurring either following a spontaneous error in DNA replication and repair or as a consequence of a chemical or physical agent) can increase the risk of developing cancer in certain individuals by several orders of magnitude (retinoblastoma, familial polyposis of the colon and some others). The multigeneration transmission of carcinogenic risk is also demonstrated by cancer prone families that are probably more frequent than originally thought, with a risk that is one order of magnitude higher than in general population. Familial clusterings of cancer may also indicate germline mutations in one or more genes. Thus the inherited predisposition to cancer that is observed today may, at least in part, be explained by the exposure to environmental noxious agents in previous generation(s). Since humans are exposed throughout life to many environmental agents, either carcinogenic or capable to enhance the progression of cancer, an understanding of the contribution of prenatal exposure to carcinogens could improve the efficacy of prevention.     

Examples of MAK values and carcinogenicity classification for mixtures

The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (MAK Commission) generally sets MAK values for single pure substances. MAK values for mixtures are only established after specific toxicological evaluation of the particular mixture. In practice, there are a few cases in which a common MAK value for the sum of all components was set, such as for mixtures of isomers (e.g. xylenes) or mixtures of related compounds (e.g. Kathon), in which the components of the mixture show comparable toxicological effects. For mixtures of isomers with different toxicological potentials, different MAK values for the single isomers are usually established. The only exception is for the isomer mixture of alpha- and beta-hexachlorocyclohexane, for which a mathematically calculated MAK value was proposed. A safe threshold cannot be established for mixtures containing substances with a genotoxic and carcinogenic potential. These mixtures are categorized either according to the proven carcinogenicity of the mixture, such as alpha-chlorinated toluenes, or according to the carcinogenic substances included, as for pyrolysis products such as coal tars.     

The outcome of intracytoplasmic sperm injection is unrelated to 'strict criteria' sperm morphology

Sperm morphology was assessed according to the 'strict criteria' established for in-vitro fertilization treatment in the semen samples used for 354 consecutive treatment cycles for intracytoplasmic sperm injection (ICSI). The semen samples were classified according to the three predictive categories of the Tygerberg strict criteria: excellent prognosis (>14% morphologically normal spermatozoa), good prognosis (4-14%) and poor prognosis (<4%). It was found that 37 (10.5%) of the ICSI cycles belonged to the excellent prognosis category, 197 (55.6%) to the good prognosis category, and 120 (33.9%) to the poor prognosis category. The outcomes of the ICSI treatments were evaluated and compared with the sperm morphology classification in order to determine whether the strict criteria could aid in predicting the outcome of ICSI. The fertilization rates in the three categories were 61.6, 66.8, and 61.9%, the pregnancy rates per oocyte retrieval 18.9, 24.9, and 28.3%, and the implantation rates 9.9, 13.0, and 14.9% respectively. No significant differences were found in fertilization, pregnancy, or implantation rates between the three prognosis categories, i.e. the poor prognosis category had an equal chance of obtaining pregnancy compared with the good prognosis category. The results indicate that strict sperm morphology is not related to the outcome of ICSI.     

Causes of cancer in Scandinavia and possible preventive measures

The purpose of this work is to address future possibilities for avoiding cancer. We elucidate the most important known causes of cancer in the Nordic countries during the second half of this century and provide estimates of the numbers of cancer cases that might be avoided by the year 2000 if those causes were effectively eliminated. Information on the pattern of carcinogenic exposures in each of the five Nordic countries and the associated relative risk estimates from the scientific literature were obtained. The numbers of avoidable cancers were assessed on the basis of this information together with the associated population attributable risk percent, PAR%, i.e. the proportion of a given cancer that can be avoided upon elimination of the causative factor. The main causes of cancer include smoking, alcohol consumption, exposure to occupational carcinogens, radiation, obesity and infection with human papillomavirus (HPV) and Helicobacter pylori. Annually, more than 18,000 cancers in men and 11,000 in women in the Nordic populations could be avoided by eliminating exposure to known carcinogens which is equivalent to 33 percent and 20 percent of all cancers arising in men and women, respectively, around the year 2000. Smoking habits account for a little more than half of these avoidable cases. Exposure to solar radiation, HPV and Helicobacter pylori, diagnostic and therapeutic radiation and consumption of alcohol play important roles in the causation of cancer, as each of these factors is linked with 1-5 percent of all cancers in men and women. Occupational exposures are also substantial causes in men (3 percent), and obesity is important in women (1 percent). In contrast, current knowledge is insufficient to give reliable estimates of the numbers of cancers that could be avoided by well-described modifications of dietary habits. These figures indicate that the most efficient way of reducing cancer morbidity would be to reduce the prevalence of exposure of the population to cancer-causing agents.     

Outcome of orthotopic liver transplantation in patients with haemophilia

As part of environmental toxicology, it is important to assess both the carcinogenic potential of xenobiotics and their mode of action on target cells. Since dysregulation of ornithine decarboxylase (ODC), a rate-limiting enzyme of polyamine biosynthesis, is considered as an early and essential component in the process of multistage carcinogenesis, we have studied the mode of ODC induction in Syrian-hamster-embryo(SHE) cells stage-exposed to carcinogens and to non-carcinogens. One-stage (5 hr) treatment of SHE cells with 50 microM clofibrate (CLF), a non-genotoxic carcinogen, or with 0.4 microM benzo(a)pyrene (BaP), a genotoxic carcinogen, slightly decreased basal ODC activity. Using the 2-stage exposure, 1 hr to carcinogen, then replacement by TPA for 5 hr, the ODC activity was higher than that obtained with TPA alone. This ODC superinduction was not observed when SHE cells were similarly pre-treated with non-carcinogenic compounds. Several environmental chemicals, pesticides, solvents, oxidizers and drugs were investigated with this SHE cell model. With one-stage exposure, some xenobiotics decreased basal ODC activity, while for others ODC changes were not noticeable. With 2-stage exposure (chemical followed by TPA), all carcinogens amplified the TPA-inducing effect, resulting in ODC superinduction. Comparative studies of the action of carcinogens and of non-carcinogens, using 2-stage exposure protocols, clearly show a close relationship between ODC induction rate and morphological transformation frequency.