Cancer species differences

The National Research Council (NRC) published a report, Science and Judgment in Risk Assessment, that critiqued the current approaches to characterizing human cancer risks from exposure to chemicals. One issue raised in the report relates to the use of default options for assessing of cancer risks. These general guidelines can be used for risk assessment when specific information about a chemical is absent. Research on 1,3-butadiene indicates that two default options may no longer be tenable Humans are as sensitive as the most sensitive animal species and the rate of metabolism is a function of body surface area rather than inherent species differences in metabolic capacity. 

Several lines of investigation have enhanced our understanding of the molecular basis of peroxisome proliferation, with important implications for cancer risk and species differences. In rodent liver, increased organ weight, peroxisome proliferation, increased replicative DNA synthesis and induction of peroxisomal and microsomal fatty... 

In the absence of definitive human data, risk assessment may have to depend on the results of cancer bioassays in laboratory animals, short-term tests, or other experimental methods. Hence the following issues must be addressed under such circumstances the ability of the test system to predict risks for man (quantitatively as well as qualitatively) the reproducibility of test results the influence of species differences in pharmacokinetics, metabolism, homeostasis, repair rates, life span, organ sensitivity, and baseline cancer rates extrapolation across dose and dose rates, and routes of exposure the significance of benign tumors fitting models to the data in order to characterize dose-incidence relationships and the significance of negative results. 

Cantor, K.P, Stewart, P.A., Brinton, L.A. Dosemeci, M. (1995) Occupational exposures and female breast cancer mortality in the United States. J. occup. environ. Med., 37, 336-348 Castro, G.D., Diaz Gomez, M.I. Castro, J.A. (1989) Species differences in the interaction... 

As discussed in the introduction to Section 2.1, there are a number of limitations in the human database for most health effects, the data are inadequate to assess the potential for humans having a particular effect. Because the human data are incomplete, hazard and risk must be extrapolated across species. A large number of adverse effects have been observed in animals, and most have been observed in every experimental animal species tested, if the appropriate dose is administered. This is illustrated in Table 2-8 for 8 major effects associated with CDD toxicity (acute lethality, hepatotoxicity, wasting syndrome, chloracne, immunotoxicity, reproductive toxicity, developmental toxicity, and cancer). With the exception of acute lethality in humans, positive responses have been observed in each tested species, when a response has been investigated. Despite the similarities in hazard response between different species, large species differences in sensitivity have been observed. Comparisons of species sensitivity demonstrate that no species is consistently sensitive or refractory for all effects and, for some effects,... 

Comparative Toxicokinetics. Available data Ifom ehronic rat inhalation bioassays show similar asbestos-induced respiratory effects to those in humans assoeiated with oeeupational exposure to asbestos (pulmonary fibrosis, lung cancer, and pleural mesothelioma), but the use of the rat data to predict human health risks from exposure to airborne asbestos has a number of areas of uneertainty, including those associated with interspecies differences in lifespan, airway morphometry, and breathing patterns. The development of rat and human lung retention models that incorporate species differences in anatomical and physiological parameters influencing deposition and clearance of asbestos fibers may decrease the... 

Jamis-Dow CA, Klecker RW, Katki AG, Collins JM. Metabolism of taxol by human and rat liver in vitro A screen for drug interactions and inter species differences. Cancer Chemother Pharmacol 1995 6 107-14. 

Gourdeau H, Leblond L, Hamelin B, et al. Species differences in troxacitabine pharmacokinetics and pharmacodynamics implications for clinical development. Clin Cancer Res. 2004 10(22) 7692-7702. 

Holden PR and Tugwood JD (1999) Peroxisome prolifera-tor-activated receptor alpha Role in rodent liver cancer and species differences. Journal of Molecular Endocrinology 22 1-8. 

Why then, since such an abundance of metabolic inhibitors is available, do so few of them find practical application Examples are the folic acid reductase inhibitors, such as aminopterin, the purine and pyrimidine analogs used as cytostatics in cancer chemotherapy and known for their high toxicity in a wide variety of species, and the organic phosphates and carbamates used as insecticides but also highly toxic to mammals. Lack of selectivity in the action of metabolic inhibitors is inherent in their mechanism of action due to the universality of biochemical processes and principles throughout nature. Selectivity in action requires species differences in biochemistry. For the antivitamins, for instance, there is not only a lack of species differences in action in addition, the fact that vitamins often serve as cofactors for a variety of enzymes is a serious drawback to endeavors to obtain agents with species-selective action. 

Although activation of the AHR by DLCs is a key event, mechanistic data indicate that AHR-mediated responses are not well conserved across species, with lower sensitivity in humans. A TEF value for a DLC based on rodent data may overestimate the potency of a DLC in humans, and this has not been considered in the current risk assessment of DLCs. Thus, the current TEF-Toxic Equivalency Quotient scheme tends to compound the conservative estimates of risk that exist within standard risk assessment approaches. Moreover mechanistic differences will now be considered by US EPA in the risk assessment of chemical carcinogens. The mechanistic data currently available for receptor-mediated DLCs and PPs clearly indicate that humans respond differently to these two classes of rodent carcinogens, and these data will need to be incorporated into cancer risk assessments for these chemicals. Full appreciation of the species differences in these receptor mechanisms will require continued development and refinement of models such as primary... 

Infection is the Achilles heel of the body and only with modern medicine has it been outrun by other diseases as the main cause of death. Therefore, there is tremendous evolutionary pressure on the immune system leading also to tremendous interindividual and species differences. The immune system also has enormous overcapacities, as it must be the last to fail. This will buffer chemical impacts on this organ system and indeed often only under additional stress of mass infection of an animal a functional deficit manifests. We have learned a lot from HIV pathophysiology about states of immunosuppression, in this case predominantly a T-cell impairment. Noteworthy, otherwise relatively rare skin cancers and reactivation of persisting infections were observed, which might suggest that... 

Pharmacokinetic models to describe, as a function of formaldehyde air concentration, the rate of formation of formaldehyde-induced DNA-protein cross links in different regions of the nasal cavity have been developed for rats and monkeys (Casanova et al. 1991 Heck and Casanova 1994). Rates of formation of DNA-protein cross links have been used as a dose surrogate for formaldehyde tissue concentrations in extrapolating exposure-response relationships for nasal tumors in rats to estimate cancer risks for humans (EPA 1991a see Section 2. 4.3). The models assume that rates of cross link formation are proportional to tissue concentration of formaldehyde and include saturable and nonsaturable elimination pathways, and that regional and species differences in cross link formation are primarily dependent on anatomical parameters (e g., minute volume and quantity of nasal mucosa) rather than biochemical parameters. The models were developed with data from studies in which... 

Shinohara, A., Saito, K., Tamazoe, Y., Kamataki, T., and Kato, R., 1986, Acetyl coenzyme A dependent activation of N-hydroxy derivatives of carcinogenic arylamines Mechanism of activation, species difference, tissue distribution, and acetyl donor specificity. Cancer Res., 46 4362-4370. 

---