Estimation Of Human Risk Research Articles

Comparative Pulmonary Toxicities and Carcinogenicities of Chronically Inhaled Diesel Exhaust and Carban Black in F344 Rats

Diesel exhaust (DE) is a known pulmonary carcinogen in rats, and the carcinogenic response is known to require the presence of soot. Many estimates of human lung cancer risk from inhaled DE have been developed from rat bioassay data or from the comparative mutagenic potencies of DE soot extract and known human chemical carcinogens. To explore the importance of the DE soot-associated organic compounds in the lung tumor response of rats, male and female F344 rats were exposed chroni cally to diluted whole DE or aerosolized carbon black (CB) 16 hr/day, 5 days/week at target particle concentrations of 2.5 mg/m3 (LDE, LCB) or 6.5 mg/m3 (HDE, HCB) or to filtered air. The CB served as a surrogate for the elemental carbon matrix of DE soot. Considering both the mass fraction of solvent-extractable matter and its mutagenicity in the Ames Salmonella assay, the mutagenicity in revertants per unit particle mass of the CB was three orders of magnitude less than that of the DE soot. Both DE soot and CB particles accumulated progressively in the lungs of exposed rats, but the rate of accumulation was higher for DE soot. In general, DE and CB caused similar, dose-related, nonneoplastic lesions. CB and DE caused significant, exposure concentration-related increases, of similar magnitudes, in the incidences and prevalences of the same types of malignant and benign lung neoplasms in female rats. The incidences of neoplasms were much lower in males than females, and the mci dences were slightly higher among DE- than CB-exposed males. Survival was shortened in the CB-exposed males, and the short ened survival may have suppressed the expression of carcinoge nicity as measured by crude incidence. Logistic regression mod eling did not demonstrate significant differences between the carcinogenic potencies of CB and DE in either gender. The re sults suggest that the organic fraction of DE may not play an important role in the carcinogenicity of DE in rats.

Mutagenesis and human genetic disease: Dominant mutation frequencies and a characterization of mutational events in mice and humans

Dominant deleterious traits are generally regarded to be the most relevant genetic endpoints when the expected increased mutational load of genetic diseases associated with exposure to mutagenic agents is considered in humans. At present, human risk estimation procedures rely on results from laboratory mammal germ-cell mutagenicity experiments as well as on data from human epidemiology and medical genetics. A comparison of the mouse and human data indicates that a small subset of loci, which when mutated result in a dominant phenotype, is contributing disproportionately to the observed mutation frequency. This is likely due to the fact that those loci with an observed high mutation frequency are inherently unstable, the function of such loci is critical, and/or the wild-type phenotype requires two copies of the normal gene (haploinsufficiency). The locus specificity of the observed spontaneous and induced mutation frequencies implies that efforts must be made to closely match those genetic endpoints screened in the mouse with the human genetic endpoints considered relevant in estimating the genetic risk after exposure to mutagenic agents. The contributions to our understanding of the organization, function, and stability of the mouse and human genomes provided by molecular biological techniques should make compliance with this restriction feasible.

An Integrated Model For Radiation Induced Cancer

Abstract Risk estimates for radiation induced cancer are based on epidemiological data, principally the Japanese A bomb survivors. These estimates for radiation are better known than for any other environmental pollutant, but they do not relate directly to exposure to low doses and low dose rates. Recent rapid advances in molecular genetics, coupled with steady gains in cellular biology, radiation physics and chemistry led to the notion that the time may not be far off when it may be possible to arrive at human cancer risk estimates entirely from laboratory data. Whether risk estimates based on laboratory data will ever replace estimates based on epidemiological studies is an open question. What is clear is that laboratory data can supplement the present risk estimates by providing information on the relative effectiveness of high LET radiations, the importance of dose rate and dose protraction, and by identifying subpopulations which are unusually sensitive or resistant to radiation carcinogenesis.

Tritium risk assessment.

Estimates of the health risks in humans from low-level exposure to tritium are presented. The health risks considered are those for cancer, genetic effects, and developmental abnormalities from exposures in utero. Because direct risk information for these effects is not available from human exposures to tritium, the following approach was used. Excess risks for the effects given following low-level exposure to x rays or gamma rays were estimated from available human epidemiological data using appropriate dose-rate effectiveness factors. These human-risk estimates for low-level x rays or gamma rays were then multiplied by the appropriate best-estimate relative biological effectiveness for tritium, taking into account differences in effectiveness of comparison radiations. The resultant lifetime risk coefficients for low-level exposure to tritiated water are as follows. For cancer mortality, the most probable risk (50th percentile) is 81 x 10(-6) mGy-1 and the 90% confidence interval is 38 to 185 x 10(-6) mGy-1. For genetic effects in the first generation after exposure the risk is 7.9 x 10(-6) mGy-1, with a 90% confidence interval of 3.8 to 16.3 x 10(-6) mGy-1. For developmental effects from low-level tritiated water exposures in utero, the risk is uncertain but is estimated to be < 400 x 10(-6) mGy-1. The risks from exposure to organically bound tritiated molecules are estimated to range from values that are similar to those for tritiated water to about a factor of 2 higher.

Nitrated polycyclic aromatic hydrocarbons: a risk assessment for the urban citizen.

Nitrated polycyclic aromatic hydrocarbons (nitro-PAHs) are formed during incomplete combustion. Sources include emissions from vehicles (mainly diesel vehicles), heating, smoking, certain types of food processing, and incomplete combustion in general. Nitro-PAHs are direct-acting mutagens, and a number of them have been shown to be carcinogens. 2-Nitrofluorene (NF) represents a model substance for the nitro-PAHs. An attempt has been made to calculate the human cancer risk due to exposure to nitro-PAHs by two different models. In the first model, genotoxic lesions were transferred to units of Gray (gamma-irradiation), and in the second model a mega study (24,000 animals) on the carcinogenicity of one metabolite of NF was used to elucidate the risk. Gamma-irradiation of the rat liver gave rise to preneoplastic foci in a dose-dependent manner, which was statistically significant. The Gray-equivalents of chemically (NF) induced foci were calculated, and from the human nitro-PAH exposure, expressed in Sievert, a human risk estimate was calculated. In the second model, an extrapolation from laboratory animals to man was performed because tumor data on 2-acetylaminofluorene (AAF), a major metabolite of NF, were available in the literature. The tumor dose-response data on AAF was linear for tested lifetime doses. The results of both models agreed, with a risk range of 0.15-49 x 10(-6) on human cancer risk for an urban citizen.

Genetic effects from exposure to hazardous agents.

Mammalian germ cell stages exhibit differences in DNA synthesis activity, capability to repair DNA damage, and chromosome-associated proteins. The sensitivity to mutation induction may be influenced by such factors as the accessibility of DNA to chemical mutagens, the interval between DNA damage induction and the next round of DNA replication, and the repair of DNA damage. Such qualitative and quantitative differences indicate the complexities of mutation induction in vivo and emphasize that no single in vitro test system can adequately represent the in vivo situation. Therefore, germ-cell mutagenesis in humans can most adequately be represented by an in vivo mammalian germ-cell test system. Information regarding the mechanisms of mutation induction in germ cells of the mouse, appropriate mutation test systems available in the mouse, as well as principles of chemical mutagenesis in the mouse and their implications for an adequate human genetic risk estimation will be discussed.

Covalent binding of styrene to DNA in rat and mouse.

Covalent binding of [7-3H]styrene (S) to DNA in vivo was measured and evaluated in a quantitative manner in order to investigate whether DNA adduct formation could form a mechanistic basis for tumor induction in a carcinogenicity bioassay. [7-3H]S was administered by inhalation in a closed chamber to male and female CD rats and B6C3F1 mice. After 4.5-6 h (rats) and 6-9 h (pools of four mice), S doses of 23-39 and 85-110 mg/kg respectively had been metabolized. DNA was purified to constant specific radioactivity which was measurable in all samples. DNA was enzymatically degraded to the 3'-nucleotides which were separated by HPLC for the detection of radiolabeled nucleotide-S adducts. The fractions with the normal nucleotides contained most of the radioactivity. In mouse liver DNA, a minute but significant level of adduct radioactivity was also detected. In the units of the Covalent Binding Index CBI = (mumol adduct/mol DNA nucleotide)/(mmol chemical/kg body wt), values of 0.05-0.09 and 0.07-0.18 were calculated for males and females respectively. In the rat, no DNA adducts were detectable in the liver at a limit of detection of 0.1 CBI units. Two of the four lung samples of the female rats showed adduct-related radioactivity corresponding to 0.07 CBI units. The CBI values are compatible with styrene 7,8-oxide as the reactive intermediate. The data are compared with CBI values and carcinogenic potencies of established genotoxic carcinogens. It is concluded that the DNA-binding potency of S is so low that significant tumor induction in a standard bioassay for carcinogenicity is unlikely to be due to DNA adduct formation alone. Consequences for a human risk estimation are discussed.

Reassessing benzene cancer risks using internal doses.

Human cancer risks from benzene exposure have previously been estimated by regulatory agencies based primarily on epidemiological data, with supporting evidence provided by animal bioassay data. This paper reexamines the animal-based risk assessments for benzene using physiologically-based pharmacokinetic (PBPK) models of benzene metabolism in animals and humans. It demonstrates that internal doses (interpreted as total benzene metabolites formed) from oral gavage experiments in mice are well predicted by a PBPK model developed by Travis et al. Both the data and the model outputs can also be accurately described by the simple nonlinear regression model total metabolites = 76.4x/(80.75 + x), where x = administered dose in mg/kg/day. Thus, PBPK modeling validates the use of such nonlinear regression models, previously used by Bailer and Hoel. An important finding is that refitting the linearized multistage (LMS) model family to internal doses and observed responses changes the maximum-likelihood estimate (MLE) dose-response curve for mice from linear-quadratic to cubic, leading to low-dose risk estimates smaller than in previous risk assessments. This is consistent with the conclusion for mice from the Bailer and Hoel analysis. An innovation in this paper is estimation of internal doses for humans based on a PBPK model (and the regression model approximating it) rather than on interspecies dose conversions. Estimates of human risks at low doses are reduced by the use of internal dose estimates when the estimates are obtained from a PBPK model, in contrast to Bailer and Hoel's findings based on interspecies dose conversion. Sensitivity analyses and comparisons with epidemiological data and risk models suggest that our finding of a nonlinear MLE dose-response curve at low doses is robust to changes in assumptions and more consistent with epidemiological data than earlier risk models.

Covalent binding of inhaled formaldehyde to DNA in the respiratory tract of rhesus monkeys: Pharmacolinetics, rat-to-monkey interspecies scaling, and extrapolation to man

DNA-protein cross-links were formed in the respiratory tract of rhesus monkeys exposed to [ 14C]formaldehyde (0.7, 2, or 6 ppm; 6 hr). Concentrations of cross-links (pmol/mg DNA) were highest in the mucosa of the middle turbinates; lower concentrations were produced in the anterior lateral wall/septum and nasopharynx. Very low concentrations were found in the larynx/trachea/carina and in the proximal portions of the major bronchi of some monkeys exposed to 6 ppm but not to 0.7 ppm. No cross-links were detected in the maxillary sinuses or lung parenchyma. The pharmacokinetics of cross-link formation in the nose were interpreted using a model in which the rate of formation is proportional to the tissue concentration of formaldehyde. The model includes both saturable and nonsaturable elimination pathways and describes regional differences in DNA binding as having an anatomical rather than a biochemical basis. Using this model, the concentration of cross-links formed in corresponding tissues of different species can be predicted by scaling the pharmacolinetic parameter that depends on minute volume (V̇) and quantity of nasal mucosal DNA ( M DNA). The concentration-response curve for the average rate of cross-link formation in the turbinates, lateral wall, and septum of rhesus monkeys was predicted from that of F-344 rats exposed under similar conditions. There was significant overlap between predicted and fitted curves, implying that V̇ and M DNA are major determinants of the rate of cross-link formation in the nasal mucosa of different species. Concentrations of cross-links that may be produced in the nasal mucosa of adult men were predicted based on experimental data in rats and monkeys. The results suggest that formaldehyde would generate lower concentrations of cross-links in the nasal mucosa of humans than of monkeys, and much lower concentrations in humans than in rats. The rate of formation of DNA-protein cross-links can be regarded as a surrogate for the delivered concentration of formaldehyde. Use of this surrogate should decrease the uncertainty of human cancer risk estimates derived by interspecies extrapolation by providing a more realistic measure of the delivered concentration at critical target sites.

Covalent Binding of Inhaled Formaldehyde to DNA in the Respiratory Tract of Rhesus Monkeys: Pharmacokinetics, Rat-to-Monkey Interspecies Scaling, and Extrapolation to Man

Covalent Bindingoflnhaled Formaldehyde to DNA in the Respiratory TractofRhesus Monkeys: Pharmacokinetics, Rat-to-Monkey Interspecies Scaling, and Extrapolation to Man. CASANOVA, M., MORGAN, K. T., STEINHAGEN, W. H., EVERITT, J. I., POPP, J. A., AND HECK, H. D'A. (1991). Fundam. Appl Toxicol 17, 409–428. DNA-protein cross-links were formed in the respiratory tract of rhesus monkeys exposed to [14C]formaldehyde (0.7, 2, or 6 ppm; 6 hr). Concentrations of cross-links (pmol/mg DNA) were highest in the mucosa of the middle turbmates; lower concentrations were produced in the anterior lateral wall/septum and nasopharynx. Very low concentrations were found in the larynx/trachea/carina and in the proximal portions of the major bronchi of some monkeys exposed to 6 ppm but not to 0.7 ppm. No cross-links were detected in the maxillary sinuses or lung parenchyma. The pharrnacokinetics of cross-link formation in the nose were interpreted using a model in which the rate of formation is proportional to the tissue concentration of formaldehyde. The model includes both saturable and nonsaturable elimination pathways and describes regional differences in DNA binding as having an anatomical rather than a biochemical basis. Using this model, the concentration of cross-links formed in correspondmg tissues of different spacies can be predicted by scaling the pharmacokinetic parameter that depends on minute volume (⁠V˙⁠) and quantity of nasal mucosal DNA (MDNA). The concentration-response curve for the average rate of cross-link formation in the turbinates lateral wall, and septum of rhesus monkeys was predicted from that of F-344 rats exposed under similar conditions. There was significant overlap between predicted and fitted curves, implying that V and MDNA are major determinants of the rate of cross-link formation in the nasal mucosa of different species. Concentrations of cross-links that may be produced in the nasal mucosa of adult men were predicted based on experimental data in rats and monkeys. The results suggest that formaldehyde would generate lower concentrations of cross-links in the nasal mucosa of humans than of monkeys, and much lower concentrations in humans than in rats. The rate of formation of DNA-protein cross-links can be regarded as a surrogate for the delivered concentration of formaldehyde. Use of this surrogate should decrease the uncertainty of human cancer risk estimates derived by interspecies extrapolation by providing a more realistic measure of the delivered concenmtion at critical target sites.

Cytogenetic analysis of mouse oocytes and one-cell zygotes as a potential assay for heritable germ cell aneuploidy

Assays are needed for detecting chemically-induced aneuploidy, for investigating the mechanisms of aneuploidy production, and for obtaining heritable germ cell data that can be used to formulate human risk estimates. In this report, we describe the results of experiments designed to study aneuploidy in metaphase II (MII) oocytes induced by intraperitoneal (i.p.) or oral dosages of colchicine, and to investigate the proportion of aneuploid oocytes transmitted to one-cell (1C) zygotes following oral administration of colchicine immediately following HCG. The proportions (and percentages) of hyperploid MII oocytes were: 1 606 (0.2) , 37 504 (7.3) , 152 731 (20.8) and 75 319 (23.5) for control, 0.2, 0.3 and 0.4 mg/kg, respectively for i.p. administration of colchicine; and 3 216 (1.4) , 8 539 (1.5) , 81 511 (15.9) , 71 398 (17.8) and 98 391 (25.1) for control, 1.0, 2.0, 3.0 and 4.0 mg/kg, respectively for oral administration of colchicine. The proportions of hyperploid 1C zygotes were 2 327 (0.6) , 21 389 (5.4) , 62 435 (14.3) and 69 438 (15.8) for control, 2.0, 3.0 and 4.0 mg/kg, respectively for oral colchicine. The proportions of hyperploid MII oocytes and 1C zygotes were significantly higher (Chi-square, P < 0.01) at each i.p. or oral dose (except 1.0 mg/kg oral) than in the controls. The frequencies of hyperploidy induced by oral doses of colchicine were greater in MII oocytes than in 1C zygotes. We also found that the frequency of developmentally delayed and polyploid 1C zygotes increased with the dose of oral colchicine. Developmentally delayed zygotes contained male-derived chromosomes and female-derived fragmented pronuclei and pronuclei with decondensed chromosomes. These results indicate that higher doses of oral colchicine are needed to induce comparable levels of aneuploidy found after i.p. administration, and that aneuploid oocytes are fertilized and reach first cleavage metaphase. In addition, colchicine induces a spectrum of events including aneuploidy, polyploidy and developmentally delayed oocytes and zygotes.

Modulating factors in the expression of radiation-induced oncogenic transformation.

Many assays for oncogenic transformation have been developed ranging from those in established rodent cell lines where morphological alteration is scored, to those in human cells growing in nude mice where tumor invasiveness is scored. In general, systems that are most quantitative are also the least relevant in terms of human carcinogenesis and human risk estimation. The development of cell culture systems has made it possible to assess at the cellular level the oncogenic potential of a variety of chemical, physical and viral agents. Cell culture systems afford the opportunity to identify factors and conditions that may prevent or enhance cellular transformation by radiation and chemicals. Permissive and protective factors in radiation-induced transformation include thyroid hormone and the tumor promoter TPA that increase the transformation incidence for a given dose of radiation, and retinoids, selenium, vitamin E, and 5-aminobenzamide that inhibit the expression of transformation. Densely ionizing alpha-particles, similar to those emitted by radon daughters, are highly effective in inducing transformations and appear to interact in a supra-additive fashion with asbestos fibers. The activation of a known dominant oncogene has not yet been demonstrated in radiation-induced oncogenic transformation. The most likely mechanism for radiation activation of an oncogene would be via the production of a chromosomal translocation. Radiation also efficiently induces deletions and may thus lead to the loss of a suppressor gene.

Factors That Modify Risks of Radiation-induced Cancer

The collective influence of biologic, physical, and other factors that modify risks of radiation-induced cancer introduces uncertainties and assumptions that limit precision of estimates of human cancer risk that can be calculated for populations exposed to low-dose radiation. The important biologic characteristics include the tissue sites and cell types, baseline cancer incidence, latent periods, time-to-tumor recognition, and individual host (e.g., age and sex) and competing etiologic influences. Physical factors include radiation dose, dose rate, and radiation quality. Statistical factors include time-response projection models, risk coefficients, and dose-response relationships. Sources that modify risk also include other carcinogens and biologic factors (e.g., hormonal conditions, immune status, hereditary factors). Discussion includes examples of known influences that modify radiation-associated cancer risks and how they have been dealt with in the risk-estimation process, including extrapolation to low doses, use of relative risk models, and other uncertainties.

Evaluation of uncertainty in input parameters to pharmacokinetic models and the resulting uncertainty in output

Physiologically-based pharmacokinetic (PBPK) models may be used to predict the concentrations of parent chemical or metabolites in tissues, resulting from specified chemical exposures. An important application of PBPK modeling is in assessment of carcinogenic risks to humans, based on animal data. The parameters of a PBPK model may include metabolic parameters, blood/air and tissue/blood partition coefficients, and physiological parameters, such as organ weights and blood flow rates. Uncertainty in estimates of these parameters results in uncertainty regarding tissue concentrations and resulting risks. Data are reviewed relevant to the quantification of these uncertainties, for a PBPK model-based risk assessment for tetrachloroethylene. Probability distributions are developed to express uncertainty in model parameters, and uncertainties are propagated by a sequence of operations that simulates processes recognized as contributing to estimates of human risk. Distributions of PBPK model output and human risk estimates are used to characterize uncertainty resulting from uncertainty in model parameters.

Choice of Dose Measure for Extrapolating Carcinogenic Risk from Animals to Humans

When estimating carcinogenic risk in humans from animal data, animal to human extrapolation is often accomplished by assuming that humans and animals are equally sensitive when dose is measured appropriately in common units in both species. This paper reports on an empirical investigation of several dose units, based on data from 23 chemicals for which both animal and human data were available. The dose units were evaluated using a measure called "bias," which represents roughly the factor by which the TD25 calculated from animal data must be multiplied to correspond, on average, to the TD25 calculated from human data. (A TD25 is the average human dose rate per unit of body weight in mg kg-1 d-1, administered between ages 20 and 65, that would cause an extra lifetime cancer risk of 25%.) Biases of greater than one mean that estimates of human risk from animal data exceeded estimates made from human data. Five dose measures are evaluated in this paper; they are based on several risk assessment methods. The resulting ranges of biases are: dose rate per surface area in mg m-2 d-1, 2.1 to 12; dose rate per unit of body weight in mg kg-1 d-1, 0.36 to 1.6; parts per million in diet, 1.1 to 6.2; cumulative dose per unit of body weight in mg kg-1 per lifetime, 13 to 84; parts per million in air, 1.1 to 4.5. These findings suggest that all of these measures of dose except dose rate per unit of body weight tend to result in overestimation of human risk.

Planning and using PB-PK models: an integrated inhalation and distribution model for nickel

A general method is presented for the use of mathematical modeling in the design, execution, and interpretation of toxicology experiments. To illustrate the use of mathematical modeling toxicology, a case study is presented of how a dosimetry model for inhaled nickel was developed for use in cancer risk estimation. A physiologically based pharmacokinetic (PB-PK) dosimetry model is used to plan animal experiments and to extrapolate nickel kinetics from animals to humans. These data are then used to estimate human lung cancer risks from human exposure to nickel aerosols. To achieve this goal, a PB-PK dosimetry model for the lung was integrated with a PB-PK dosimetry model for the internal organs. Nickel removal from the lung was found to be saturable and to follow Michaelis-Menten kinetics. The PB-PK lung dosimetry model was used to design both short-term (single exposures) and long-term (multiple intermittent exposures) needed to validate the parameters ( K m and V max) of the lung dosimetry model. A constant infusion experiment was planned using the PB-PK modeling approach to measure the distribution and elimination of intravenously administered nickel. The two PB-PK models were integrated to estimate the fate of nickel after inhalation and are being used to plan experiments for other routes of exposure such as ingestion of drinking water and dermal contact. The integrated model has been used to calculate a human cancer risk estimate in combination with short-term genotoxic experiments. Using PB-PK models in toxicology, as illustrated here, conserves experimental animals, aids in understanding new physiological phenomena (such as saturable clearance from the lung), incorporates in vitro tests with in vivo experiments, and provides a means of extrapolation to human health risks from multiple routes of exposure. Introducing the concepts of mathematical modeling into toxicity experiments at the beginning of the experiment improves the usefulness of the experiments in risk estimation. PB-PK models are suggested as a new basis for experimental design in toxicology.

Opportunities for Improving Techniques for Interspecies Extrapolation in the Risk Assessment Process

Quantitative estimates of human carcinogenic risk from chemical exposure are currently derived primarily from linearized multistage model analyses of the tumor response as observed in chronic laboratory animal bioassays versus administered dose. The numerous ad hoc assumptions that provide a rationale for this generic approach to carcinogenic risk assessment can only be evaluated critically when mechanistic data directly relevant to the low-dose and interspecies extrapolation problems are available. Clear needs exist to develop such ancillary data bases and the means for explicitly incorporating them into the risk estimation process. Target site dosimetry provides one useful organizing concept. Physiological response modeling can account systematically for interspecies variations in the distribution and disposition of chemicals in relation to external measures of exposure. Direct measurements of interactions of chemicals and their metabolites with specific target macromolecules can provide sensitive and biologically meaningful exposure indices. Alternatively, quantitation of toxic effects such as altered cell regulation and differentiation can serve the same purpose. Virus and oncogene activation, DNA damage and repair, and enhanced cell proliferation provide additional biological markers of exposure. They may also comprise critical elements of the carcinogenic process. Identification of the actual mechanisms involved should eventually lead to the development of risk assessment models that adequately reflect the unique biological and toxicological characteristics of different species-chemical combinations.

Opportunities for improving techniques for interspecies extrapolation in the risk assessment process.

Quantitative estimates of human carcinogenic risk from chemical exposure are currently derived primarily from linearized multistage model analyses of the tumor response as observed in chronic laboratory animal bioassays versus administered dose. The numerous ad hoc assumptions that provide a rationale for this generic approach to carcinogenic risk assessment can only be evaluated critically when mechanistic data directly relevant to the low-dose and interspecies extrapolation problems are available. Clear needs exist to develop such ancillary data bases and the means for explicitly incorporating them into the risk estimation process. Target site dosimetry provides one useful organizing concept. Physiological response modeling can account systematically for interspecies variations in the distribution and disposition of chemicals in relation to external measures of exposure. Direct measurements of interactions of chemicals and their metabolites with specific target macromolecules can provide sensitive and biologically meaningful exposure indices. Alternatively, quantitation of toxic effects such as altered cell regulation and differentiation can serve the same purpose. Virus and oncogene activation, DNA damage and repair, and enhanced cell proliferation provide additional biological markers of exposure. They may also comprise critical elements of the carcinogenic process. Identification of the actual mechanisms involved should eventually lead to the development of risk assessment models that adequately reflect the unique biological and toxicological characteristics of different species-chemical combinations.

Estimation of human reproductive risk from animal studies: determination of interspecies extrapolation factors for steroid hormone effects on the male.

The problem of extrapolating effects of reproductive toxins on experimental animals to predict the doses that would produce infertility in human males is discussed using published data on effects of testosterone and estradiol on sperm production in the rat, rabbit, rhesus monkey, ram, stallion, and humans. This analysis indicates that calculation of the dose of testosterone that reduces human sperm counts by a given percentage is best done using the dose administered to laboratory animals expressed on the basis of body weight, as opposed to some other parameter such as body surface area. A survey of the available data in the literature indicates the incompleteness of the data set and the specific information needed to improve the basis for extrapolation. Nevertheless, we can predict from studies on laboratory animals the dose of testosterone necessary to reduce sperm counts in humans within a factor of 2.

Forestomach carcinogens: pathology and relevance to man.

Squamous cell carcinomas of the forestomach have been observed in many carcinogenicity studies in rodents, especially after oral or gavage exposure. The histopathological diagnosis of forestomach lesions and the relevance of the data for human risk estimation can be controversial. The pathological classification may be troublesome because of the low-grade malignancy and the pseudoepitheliomatous hyperplasia that may develop after ulceration and inflammation. For human risk estimation it is important to understand the mechanism of action; this is illustrated by examples using butylated hydroxyanisole, methyl bromide, and epichlorohydrin. Another feature that complicates risk estimation is the absence of a homologue for the forestomach in man. The potential risk from non-genotoxic forestomach carcinogens in man involves exposure of the mouth, pharynx, and esophagus at dose levels that exert irritating action. It is assumed that exposure to non-genotoxic chemicals at concentrations far below those having irritating potential is not hazardous to humans.