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Since 1975, the IARC has been preparing a series of volumes entitled "Environmental Carcinogens: Selected Methods of Analysis" (IARC Manual series) of which the purposes are to assist analysts, epidemiologists and regulatory authorities in planning or performing exposure measurements that are truly comparable between different studies. The Manual series provides expert information within each volume on multi-media sampling, methods of analyses and some background of epidemiology, metabolism, use/occurrence for a group of known or suspect carcinogens. So far, eleven volumes have been published or are in preparation on the following subjects: N-nitrosamines, vinyl chloride, PAH, aromatic amines, mycotoxins, N-nitroso compounds, volatile halogenated hydrocarbons, metals, passive smoking, benzene and alkylated benzenes, dioxins, PCDFs and PCBs. The presentation will discuss needs and priorities for use of analytical chemistry in estimating exposures of apparently greatest relevance to cancer causation, i.e. the approach to developing this series. Indications from epidemiology, evaluations of carcinogenic risk to humans, and recent developments in total exposure assessment are that new methods and matrices need more emphasis, e.g. as with biochemical dosimetry, exhaled breath, and in indoor air.

Much work has been carried out on N-nitroso compounds but their role in human pathology has still to be elucidated. We cannot extrapolate experimental data to the human situation but we do have indirect evidence that nitroso compounds can be carcinogens in man. Although some nitrosamines are organ-specific, the nitroso group induces the development of many different types of cancer in animals It is probable that the same phenomenon occurs in human pathology, and we cannot therefore expect to have special case reports on their carcinogenicity in man. Therefore, an alternative approach to the study of the role of nitrosamines in human pathology would be to establish a correlation between cancer morbidity in some regions and amounts of N-nitroso compounds in the environment. In view of the complexity of the problem of in vivo nitrosamine formation, it is more realistic nowadays to measure exogenous nitrosamines. Many laboratories are currently engaged on studies on N-nitroso compounds, although systematic information on their presence in the environment is scant. Furthermore, the data acquired by different laboratories has been obtained using a variety of methods for sampling, storage, clean-up and identification and estimation, with the result that it is not known to what extent these results are comparable.Therefore, the standardization and determination of comparability of methods for the identification of N-nitroso compounds is the first step towards their quantitation in the environment. Adequate methods are now available for the determination of volatile nitrosamines, down to the mug/dg level, but methods for non-volatile nitrosamines are still in the development stages. In order to avail all interested laboratories of information on analytical methods for volatile nitrosamines, IARC's analytical chemistry laboratory has organized a three part collaborative study using samples of canned luncheon meat. The results of this study were encouraging, and the European Sub-Committee for the Guidance of Collaborative Studies, at its last meeting, recommended that such studies be continued and extendedto include non-volatile nitrosamines. In parallel with the perfection of analytical techniques, IARC has initiated studies on the measurement of volatile nitrosamines in the environment in conjuction with the epidemiological studies on oesophageal cancer at present being carried out. The data collected up to now is far from being complete but it is important in that it represents the first step towards the evaluation of the risk to health of N-nitroso compounds, which constitute a part of the total carcinogenic load in the human environment.

A short review on environmental carcinogenesis by chemicals is given. Problems related with the determination of carcinogenicity of chemicals are mentioned. Some critical factors in the monitoring of environmental carcinogens are discussed in relation to a quantification of human exposure to such compounds. An attempt at risk evaluation is made for polycyclic aromatic hydrocarbons, vinyl chloride, N-nitroso compounds and aflatoxins. It is concluded that there is a "threshold dose" for individual carcinogens that does not lead to tumor induction within the normal life span. The probability of multifactorial cause of human cancer by environmental carcinogens, however, does not allow the definition of "safe" levels of such compounds in view of syncarcinogenic and other enhancing and/or modifying effects.

Chromatophoromas in the croaker nibe, Nibea mitsukurii, are common neoplasms in feral fish which inhabit the shallow water in a unique geographic distribution along the Pacific coast of Japan. We undertook surveys of the epizootiology of tumor-bearing fish at 25 sites. The highest tumor incidence occurred at the station near the mouth of the Kumano river and was 47% (1,415 of 2,991). The incidence at 2 adjacent survey stations located approximately 18 and 30 km away were 2.7 and 2.5%, respectively. At the other survey stations, no tumor incidences were recorded or they were less than 5%. During the course of experimental studies on the chromatophoromas using tank-reared nibe, we found that nifurpirinol (NP), a drug used for the treatment of fish diseases, might also induce the chromatophoromas in the fish, as well as N-methyl-N'-nitro-N-nitrosoguanidine and 7,12-dimethylbenz[alpha]anthracene. Therefore, tank-reared nibe 5 months of age were divided into 4 groups of about 50 each and exposed to water containing 0, 0.5, 1, or 2 ppm NP, respectively, fourteen times for 1 hour each time. Three hundred nibe were kept as untreated controls. The incidences of chromatophore hyperplasia or neoplasia per group at 13 months were as follows: the untreated: 2.9% (6 of 204), 0 ppm: 5.3% (2 of 38), 0.5 ppm: 73% (36 of 49), 1 ppm: 87% (20 of 23), and 2 ppm: 100% (2 of 2). These and other results led us to believe that 1) NP is a carcinogen, 2) nibe have a high susceptibility to induction of chromatophoromas by chemical carcinogens, and 3) some environmental chemicals are causal factors in the hyperendemic occurrences of the tumors in wild nibe.

The incidence of primary liver cancer in the countries of tropical Africa is the highest in the world. There is a growing belief that the relatively high prevalence of hepatocellular carcinoma in Nigeria may have a multiple chemical factor etiology in such forms as food contaminants, herbal teas, and environmental chemicals. Major chemical toxins and carcinogens that have been identified so far in the tropical environment include sapotoxin, cycasin, mushroom toxin, capsaicin, oxalic acid, prussic acid, fluorooleic acid, N-nitroso compounds, aflatoxin, palmotoxin, pyrrolizidine alkaloids, quinine, DDT, and cyclamate.

Carbon blacks used in tire production have been examined for their polycyclic aromatic hydrocarbons (P.A.H.) content. The analytical procedures commonly adopted are discussed. The results obtained show that, A benzene extraction time of 250 hours is necessary to obtain complete extraction, but for practical purposes, an extraction time of 150 hours is sufficient to extract more than 95% of the PAH. It is possible to identify two classes of blacks in regard to extractables. The one class provides extractables in the range of 200--400 micrograms/g; the second class, in the range of 1000--2000 micrograms/g. No P.A.H. were detected by direct injection of carbon black into the mass spectrograph at 200 degrees C, 10(-6) torr. This was probably due to the very strong bonding to the black particles. The P.A.H. contribute a relative constant percentage of the benzene extracts. It is reasonably possible to exclude any carcinogenic risk to personnel, in a working environment, with an airborne carbon black concentration equal to or less than 3.5 mg/m3, due to the very low P.A.H. content of carbon black and to the very strong P.A.H. bonding to the black particles.

This paper evaluates the influence of the quality of drinking water on the incidence of malignant stomach cancer. Both the author's own data and the data collected from published papers are used in this evaluation. The conclusion is that the quality of drinking water can have some influence on the frequency of stomach cancer incidence, especially among the population of autochthons (who have been using such water for a long time). However, taking into consideration all papers quoted here, it seems that there are also various other factors which can influence the incidence of stomach cancer.

Concentrations of benz(a)pyrene (BP) and 15 other polycyclic aromatic hydrocarbons (PAH) in soil with forage plants (lucerne) irrigated by biologically purified mixed domestic and industrial (coke-chemical) sewage from collection pond did not exceed those in control soil (irrigated by relatively clean fresh water) and were lower than in nonirrigated one, which is due, probably, to PAH oxidation by soil-proper microflora activated in humid soil polluted by PAH. BP content in control and experimental samples of lucerne coincide within +/- 25% limits.

The paper presents experimental data on different polycyclic aromatic hydrocarbons (PAH) in water, bottom sediments and algae as well as evidence available in literature on their content in exhausts of automobiles, oil shale industry and power station. Attempts are made to reveal differences in sources of the environment pollution with allowance for different PAH/benzo(a)pyrene percentage ratio, but as the PAH ratios are relatively similar in different pollution sources this attempt was a failure.

The problem of the presence of carcinogens in the environment has become of considerable concern to the public, as it has been to the biomedical community for some time. The burden of identifying carcinogenic agents and determining threshold levels, if they exist, falls upon the scientific community. Particular care must be exercised in the design, conduct and analysis of experiments directed toward the identification of carcinogens. The data generated from such tests provides the basis for regulatory decisions by governmental authorities. The advice provided by scientists must be based on sound data. There have been instances, however, and there will be others, in which biological variability and the limits of sensitivity of our tests will give equivocal results. It is the duty of scientists to bring such uncertainties to the attention of the public while working towards the development of more sensitive and precise techniques.

Factors contributing to urban differences in cancer mortality rates are difficult to specify because of migration and the delay between exposure to carcinogens and manifestations of the disease. Proxy measures for prior migration, motor vehicle emissions, industrial pollution, factors in the water supplies, and climate, explain more than half the intercity variation in age-adjusted cancer mortality rates among 98 cities in the U.S. in 1970. The potential importance of these environmental factors as the "urban factor" in cancer is discussed.

With data from the Iowa Cancer Registry, age-adjusted sex-specific cancer incidence rates for the years 1969-1981 were determined for towns with a population of 1,000-10,000 and a public water supply from a single stable ground source. These rates were related to levels of volatile organic compounds and metals found in the finished drinking water of these towns in the spring of 1979. Results showed association between 1,2 dichloroethane and cancers of the colon and rectum and between nickel and cancers of the bladder and lung. The effects were most clearly seen in males. These associations were independent of other water quality and treatment variables and were not explained by occupational or other sociodemographic features including smoking. Because of the low levels of the metals and organics, the authors suggest that they are not causal factors, but rather indicators of possible anthropogenic contamination of other types. The data suggest that water quality variables other than chlorination and trihalomethanes deserve further consideration as to their role in the development of human cancer.

Coke oven workers are exposed to high levels of carcinogenic polycyclic aromatic hydrocarbons, including benzo[a]pyrene (B[a]P), and are at increased risk of lung cancer. Since B[a]P is enzymatically activated to 7 beta,8 alpha-dihydroxy(9 alpha, 10 alpha)epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (B[a]PDE) that forms adducts with DNA, the presence of these adducts was measured in DNA from peripheral blood lymphocytes by synchronous fluorescence spectrophotometry and enzyme radioimmunoassay. Approximately two-thirds of the workers had detectable levels of B[a]PDE-DNA adducts. Antibodies to the DNA adducts were also found in the serum of 27% of the workers. B[a]PDE-DNA adducts were not detectable in lymphocytes and antibodies to the adducts were not detected in sera from a control group of nonsmoking laboratory workers. DNA adducts and/or antibodies to the adducts indicate exposure to B[a]P and its metabolic activation to the carcinogenic metabolite that covalently binds to and damages DNA. Detection of adducts and antibodies to them may also be useful as internal dosimeters of the pathobiological effective doses of chemical carcinogens.

Tissue doses of cancer initiators/mutagens are suitably monitored through hemoglobin adducts formed in vivo, but the use of this method has been hampered by a lack of sufficiently simple and fast procedures. It was previously observed that when the N-terminal amino acid in hemoglobin, valine, is alkylated it is cleaved off by the Edman sequencing reagent, phenyl isothiocyanate, in the neutral-alkaline coupling medium, as opposed to the acidic medium required by normal amino acids. Based on this principle, conditions for a functioning procedure for gas chromatography/mass spectrometry (GC/MS) determination of N-terminal alkylvalines in hemoglobin were worked out. Derivatizing the protein in formamide solution with pentafluorophenyl isothiocyanate, using a 2H-alkylated protein as internal standard, and applying on-column injection during analysis, permit reproducible determination of hydroxyethylvaline and other adducts down into the dose range where cancer risks may be considered acceptably low.

Complete control of carcinogenic hazards in industry is an unrealistic concept. Industry, nevertheless, has a duty to give careful consideration to existing carcinogenic hazards, and to the possibility of new ones. Only well recognized hazards can be subjected to legislative control. Industry must take into account published experimental and epidemiological data, along with physical and chemical considerations related to specific agents, and, where necessary, introduce appropriate preventive measures.

After some short remarks on the history of the methods of determining the acceptable daily intake (ADI), an aim nowadays extended to chemicals in the environment, we briefly describe the procedures presently in use. The increasing importance of genetic pharmacology is referred to with respect to the data of the Food Safety Council. Finally the problems of the ADI of substances with carcinogenic and allergic or sensitizing effects are discussed.

As the numbers and production of environmental pollutants and hazardous industrial compounds increase, the necessity for monitoring the environment and workplace to avoid or to limit human exposure to toxic substances becomes more urgent. In support of the occupational safety program at the National Center for Toxicological Research, very sensitive and specific radioimmunoassays for measuring two known animal carcinogens, 2-acetylaminofluorene and diethylstilbestrol and their metabolites were developed. Radioimmunoassay (RIA) techniques offer unique advantages over ixisting methodologies in the field of toxicology; these include exquisite specificity and sensitivity, simplicity in sample handling and rapid analysis. These RIAs are currently being used for monitoring possible human exposure to carcinogenic compounds.

The chemical composition and microbial mutagenicity of aerosols generated by nebulizing two coal oils (solvent refined coal [SRC]-I process solvent [PS] and SRC-II heavy distillate) were found to vary with particle size. Significant quantities of the most volatile components of PS were also present as vapors. Evaporation and condensation processes in oil deposited on surfaces as well as in the aerosol are believed to be important in determining the observed composition changes. Complete physical and chemical characterization of the aerosol should be included in inhalation studies of complex materials since the animals may be exposed to material of quite different composition than that placed in the generator initially.

In 1971, waste oil containing 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was sprayed for dust control on a number of residential, recreational, and work areas in Missouri. In several of them, the level and extent of environmental contamination were not known until late 1982 or 1983. Extrapolation from existing toxicological data indicated the potential for substantial adverse health effects in highly exposed populations. As a result, the Missouri Division of Health and the Centers for Disease Control initiated close collaboration with the Environmental Protection Agency (EPA) on review and evaluation of environmental data, the development of health advisories to EPA on the need for remedial or preventive actions at specific contaminated sites, a health education effort for the medical community and general public, establishment of a dermatological screening clinic, establishment of a central listing of potentially exposed persons through administration of a health effects survey questionnaire, and a pilot medical study of a "highest risk" cohort. Strategies for additional interventions will continue to be based on findings derived from this first phase of the investigation.

Past studies with animals have demonstrated that 4-aminobiphenyl (ABP) administration results in the formation of appreciable amounts of adducts between the carcinogen and both serum albumin and hemoglobin. The hemoglobin adduct is relatively stable in vivo, but may be readily hydrolyzed in vitro to regenerate ABP. The formation of this adduct reflects a mixed-function oxidase-mediated metabolic pathway operating directly on the amine. The predominant albumin adduct, 3-(tryptophan-N1-yl)-4-acetylaminobiphenyl, reflects the contribution of N-acetyltransferase activity as well as mixed function oxidase activity to the overall metabolism. The simultaneous measurement of these two different adducts thus offers an opportunity to investigate the role of both ABP and acetylator phenotype in bladder carcinogenesis. An analytical method, using gas chromatography coupled with electron capture detection, was developed to quantitate ABP adducted to hemoglobin.

A considerable accumulation of benzo(a)pyrene (BP) in the bottom ground (approx. 10,000 times that in the water) threatens with secondary pollution of water reservoirs with this compound. Laboratory experiments were carried out to establish the main regularities of BP distribution in the water-bottom ground system. It was shown that, besides BP degradation, BP sorption in the bottom ground plays an important role in this system. Under normal environmental conditions, the bottom ground should not become a source of secondary pollution.

Polynuclear hydrocarbon pollution is controlled sistematically in an industrial area in Genoa town. Quantitative and qualitative evaluation was carried out by gas chromatographic technique. First results show a remarkable intake of such pollutants in the air. The used sample collection allowed also the evaluation of polynuclear hydrocarbon levels according to the day hours.

A total of 100 passenger cars were tested with regard to the amount of polycyclic aromatic hydrocarbons (PAH) emitted during the EUROPA-Test (E.-Test, simulate city driving; 4 times 195 s). As determined by frequency of registration, the 20 most common car models were chosen. Each model was represented by 5 cars. The total amount of selected 14 PAH emitted by all test vehicles during an E.-test is in the range of 1-16 mg. As can be seen from the average of fuel consumption (409.4 g/E.-test) and benzo(a)pyrene emission (41.6 mug/E.-test), 1000 kg of burned fuel yield 101 mg of benzo(a)pyrene. Based on the consumption of gasoline in 1973 in West Germany (18508200 tons), an annual amount of 1.85 tons of benzo(a)pyrene is produced by gas engine vehicles. However, the biological effect of the automobile exhaust is still larger because it contains additional carcinogenic PAH. - A statistical evaluation of the results shows that different car models can not be distinguish by their PAH emission. When evaluating individual vehicles after 5 repeated E.-tests, the margin of error for any single PAH is between 6.3-10.9% (variation coefficient) for this car. A larger margin of error is obtained by pooling 5 different vehicles of the same model.