[show abstract][hide abstract] ABSTRACT: The leading 20th century proponent for primary prevention of environmental cancer was Dr. Lorenzo Tomatis, the former Director of the International Agency for Research on Cancer and founder of the IARC Monographs program. This paper is dedicated to the memory of Dr. Tomatis--eminent scientist, scholar, teacher, humanitarian, and public health champion--and includes many perspectives that he promoted throughout his career, with original quotations from some of his scientific writings on primary prevention of environmental cancer. Any attempt by us to simply summarize his views would only detract from the power and logic of his language."Cancer still remains a mainly lethal disease. Primary prevention remains the most relevant approach to reduce mortality through a reduction in incidence".
Environmental Health 01/2011; 10 Suppl 1:S14. · 2.71 Impact Factor
[show abstract][hide abstract] ABSTRACT: In National Toxicology Program 2-year studies, hexavalent chromium [Cr(VI)] administered in drinking water was clearly carcinogenic in male and female rats and mice, resulting in small intestine epithelial neoplasms in mice at a dose equivalent to or within an order of magnitude of human doses that could result from consumption of chromium-contaminated drinking water, assuming that dose scales by body weight(3/4) (body weight raised to the 3/4 power). In contrast, exposure to trivalent chromium [Cr(III)] at much higher concentrations may have been carcinogenic in male rats but was not carcinogenic in mice or female rats. As part of these studies, total chromium was measured in tissues and excreta of additional groups of male rats and female mice. These data were used to infer the uptake and distribution of Cr(VI) because Cr(VI) is reduced to Cr(III) in vivo, and no methods are available to speciate tissue chromium. Comparable external doses resulted in much higher tissue chromium concentrations following exposure to Cr(VI) compared with Cr(III), indicating that a portion of the Cr(VI) escaped gastric reduction and was distributed systemically. Linear or supralinear dose responses of total chromium in tissues were observed following exposure to Cr(VI), indicating that these exposures did not saturate gastric reduction capacity. When Cr(VI) exposure was normalized to ingested dose, chromium concentrations in the liver and glandular stomach were higher in mice, whereas kidney concentrations were higher in rats. In vitro studies demonstrated that Cr(VI), but not Cr(III), is a substrate of the sodium/sulfate cotransporter, providing a partial explanation for the greater absorption of Cr(VI).
[show abstract][hide abstract] ABSTRACT: Hexavalent chromium [Cr(VI)] is a human carcinogen after inhalation exposure. Humans also ingest Cr(VI) from contaminated drinking water and soil; however, limited data exist on the oral toxicity and carcinogenicity of Cr(VI).
We characterized the chronic oral toxicity and carcinogenicity of Cr(VI) in rodents.
The National Toxicology Program (NTP) conducted 2-year drinking water studies of Cr(VI) (as sodium dichromate dihydrate) in male and female F344/N rats and B6C3F1 mice.
Cr(VI) exposure resulted in increased incidences of rare neoplasms of the squamous epithelium that lines the oral cavity (oral mucosa and tongue) in male and female rats, and of the epithelium lining the small intestine in male and female mice. Cr(VI) exposure did not affect survival but resulted in reduced mean body weights and water consumption, due at least in part to poor palatability of the dosed water. Cr(VI) exposure resulted in transient microcytic hypochromic anemia in rats and microcytosis in mice. Nonneoplastic lesions included diffuse epithelial hyperplasia in the duodenum and jejunum of mice and histiocytic cell infiltration in the duodenum, liver, and mesenteric and pancreatic lymph nodes of rats and mice.
Cr(VI) was carcinogenic after administration in drinking water to male and female rats and mice.
Environmental Health Perspectives 06/2009; 117(5):716-22. · 7.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: The widespread detection of perfluoroalkyl acids and their derivatives in wildlife and humans, and their entry into the immature brain, raise increasing concern about whether these agents might be developmental neurotoxicants.
We evaluated perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorooctane sulfonamide (PFOSA), and perfluorobutane sulfonate (PFBS) in undifferentiated and differentiating PC12 cells, a neuronotypic line used to characterize neurotoxicity.
We assessed inhibition of DNA synthesis, deficits in cell numbers and growth, oxidative stress, reduced cell viability, and shifts in differentiation toward or away from the dopamine (DA) and acetylcholine (ACh) neurotransmitter phenotypes.
In general, the rank order of adverse effects was PFOSA > PFOS > PFBS approximately PFOA. However, superimposed on this scheme, the various agents differed in their underlying mechanisms and specific outcomes. Notably, PFOS promoted differentiation into the ACh phenotype at the expense of the DA phenotype, PFBS suppressed differentiation of both phenotypes, PFOSA enhanced differentiation of both, and PFOA had little or no effect on phenotypic specification.
These findings indicate that all perfluorinated chemicals are not the same in their impact on neurodevelopment and that it is unlikely that there is one simple, shared mechanism by which they all produce their effects. Our results reinforce the potential for in vitro models to aid in the rapid and cost-effective screening for comparative effects among different chemicals in the same class and in relation to known developmental neurotoxicants.
Environmental Health Perspectives 06/2008; 116(6):716-22. · 7.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: As Dobzhansky wrote, nothing in biology makes sense outside the context of the evolutionary theory, and this truth has not been sufficiently explored yet by medicine. We comment on Shanks and Pyles' recently published paper, Evolution and medicine: the long reach of "Dr. Darwin", and discuss some recent advancements in the application of evolutionary theory to carcinogenesis. However, we disagree with Shanks and Pyles about the usefulness of animal experiments in predicting human hazards. Based on the darwinian observation of inter-species and inter-individual variation in all biological functions, Shanks and Pyles suggest that animal experiments cannot be used to identify hazards to human health. We claim that while the activity of enzymes may vary among individuals and among species, this does not indicate that critical events in disease processes occurring after exposure to hazardous agents differ qualitatively between animal models and humans. In addition, the goal is to avoid human disease whenever possible and with the means that are available at a given point in time. Epidemics of cancer could have been prevented if experimental data had been used to reduce human exposures or ban carcinogenic chemicals. We discuss examples.
Philosophy Ethics and Humanities in Medicine 02/2008; 3:6.
[show abstract][hide abstract] ABSTRACT: Conflicting views have been expressed frequently on assessments of human cancer risk of environmental agents based on animal carcinogenicity data; this is primarily because of uncertainties associated with extrapolations of toxicologic findings from studies in experimental animals to human circumstances. Underlying these uncertainties are issues related to how experiments are designed, how rigorously hypotheses are tested, and to what extent assertions extend beyond actual findings. National and international health agencies regard carcinogenicity findings in well-conducted experimental animal studies as evidence of potential carcinogenic risk to humans. Controversies arise when both positive and negative carcinogenicity data exist for a specific agent or when incomplete mechanistic data suggest a possible species difference in response. Issues of experimental design and evaluation that might contribute to disparate results are addressed in this article. To serve as reliable sources of data for the evaluation of the carcinogenic potential of environmental agents, experimental studies must include a) animal models that are sensitive to the end points under investigation; b) detailed characterization of the agent and the administered doses; c) challenging doses and durations of exposure (at least 2 years for rats and mice); d) sufficient numbers of animals per dose group to be capable of detecting a true effect; e) multiple dose groups to allow characterization of dose-response relationships, f) complete and peer-reviewed histopathologic evaluations; and g) pairwise comparisons and analyses of trends based on survival-adjusted tumor incidence. Pharmacokinetic models and mechanistic hypotheses may provide insights into the biological behavior of the agent; however, they must be adequately tested before being used to evaluate human cancer risk.
Environmental Health Perspectives 02/2008; 116(1):130-5. · 7.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: 1,3-Butadiene and chloroprene are multisite carcinogens in B6C3F1 mice with the strongest tumor response being the induction of lung neoplasms in females. Incidence of brain tumors in mice exposed to 1,3-butadiene was equivocal. This article reviews the efforts of our laboratory and others to uncover the mechanisms of butadiene and chloroprene induced lung and brain tumor responses in the B6C3F1 mouse. The formation of lung tumors by these chemicals involved mutations in the K-ras cancer gene and loss of heterozygosity in the region of K-ras on distal chromosome 6, while alterations in p53 and p16 were implicated in brain tumorigenesis.
[show abstract][hide abstract] ABSTRACT: Dibromoacetic acid (DBA) is a water disinfection byproduct formed by the reaction of chlorine oxidizing compounds with natural organic matter in water containing bromide. Male and female F344/N rats and B6C3F(1) mice were exposed to DBA in drinking water for 2 weeks (N=5), 3 months (N=10), or 2 years (N=50). Concentrations of DBA in drinking water were 0, 125, 250, 500, 1000, and 2000mg/L in the 2-week and 3-month studies, and 0, 50, 500, and 1000mg/L in the 2-year studies. Toxic effects of DBA in the prechronic studies were detected in the liver (hepatocellular cytoplasmic vacuolization in rats and mice) and testes (delayed spermiation and atypical residual bodies in male rats and mice, and atrophy of the germinal epithelium in rats). In the 2-year studies, neoplasms were induced at multiple sites in rats and mice exposed to DBA; these included mononuclear cell leukemia and abdominal cavity mesothliomas in rats, and neoplasms of the liver (hepatocellular adenoma or carcinoma and hepatoblastoma) and lung (alveolar adenoma or carcinoma) in mice. The increase in incidence of hepatocellular neoplasms in male mice was significant even at the lowest exposure concentration of 50mg/L, which is equivalent to an average daily dose of approximately 4mg/kg. These studies provide critical information for future re-evaluations of health-based drinking water standards for haloacetic acids.
[show abstract][hide abstract] ABSTRACT: Toxicology studies of diethanolamine were conducted in male and female F344 rats for 13 weeks' duration to characterize and compare effects of exposure in the drinking water with those caused by topical application. Doses of diethanolamine ranged from 160 to 5000 ppm in the drinking water study (equivalent to daily doses of 25–440 mg kg−1 in males and 15–240 mg kg−1 in females) and from 32 to 500 mg kg−1 in the topical application study. Dose-dependent toxic effects due to exposure to diethanolamine included hematological changes (a poorly regenerative, microcytic anemia), as well as toxic responses in the kidney (increased weight, tubular necrosis, decreased renal function, and/or tubular mineralization), brain and spinal cord (demyelination), testis (degeneration of the seminiferous tubules) and skin (site of application: ulceration, inflammation, hyperkeratosis and acanthosis). A no-observed-adverse-effect level was not achieved for hematological changes, nephropathy or hyperkeratosis of the skin. Differences in dose-response between the drinking water and topical application exposures were attributed largely to the limited dermal absorption of this chemical.
[show abstract][hide abstract] ABSTRACT: Toxicology studies of diethanolamine were conducted in male and female B6C3F1 mice to characterize and compare effects of exposure in the drinking water with those caused by topical application and to compare responses in mice to those observed in rats. Each study consisted of five dose groups plus controls and the size of each group was 10 animals per sex. Doses of diethanolamine ranged from 630 to 10 000 ppm in the drinking water study (approximately equivalent to daily doses of 100–1700 mg kg−1 in males and 140–1100 mg kg−1 in females) and from 80 to 1250 mg kg−1 in the topical application study. Exposure to diethanolamine caused dose-dependent toxic effects in the liver (hepatocellular cytological alterations and necrosis), kidney (nephropathy and tubular epithelial necrosis in males), heart (cardiac myocyte degeneration) and skin (site of application: ulceration, inflammation, hyperkeratosis, and acanthosis). Cytological alterations in the liver consisted of multiple hepatocyte changes, including enlarged cells that were frequently multinucleated, increased nuclear pleomorphism, increased eosinophilia and disruption of hepatic cords. A no-observed-adverse-effect level (NOAEL) was not achieved for hepatocellular cytological alterations or for acanthosis in the skin.
[show abstract][hide abstract] ABSTRACT: The nervous system of the B6C3F1 mouse has rarely been a target for chemical carcinogenesis in the National Toxicology Program (NTP) bioassays. However, 6 malignant gliomas and 2 neuroblastomas were observed in B6C3F1 mice exposed to 625 ppm 1,3-butadiene (NTP technical reports 288 and 434). These mouse brain tumors were evaluated with regard to the profile of genetic alterations that are observed in human brain tumors. Alterations in the p53 tumor suppressor gene were common. Missense mutations were observed in 3/6 malignant gliomas and 2/2 neuroblastomas and were associated with loss of heterozygosity. Most of the mutations occurred in exons 5-8 of the p53 gene and were G-->A transitions, and did not involve CpG sites. Loss of heterozygosity at the Ink4a/Arf gene locus was observed in 5/5 malignant gliomas and 1/1 neuroblastoma, while the PTEN(phosphatase and tensin homologue) gene locus was unaffected by deletions. One of 2 neuroblastomas had a mutation in codon 61 of H-ras, while H-ras mutations were not observed in the malignant gliomas examined. Only 1 brain tumor has been reported from control mice of over 500 NTP studies. This malignant glioma showed no evidence of alterations in the p53 gene or K- and H-ras mutations. It is likely that the specific genetic alterations observed were induced or selected for by 1,3-butadiene treatment that contributed to the development of mouse brain tumors. The observed findings are similar in part to the genetic alterations reported in human brain tumors.
[show abstract][hide abstract] ABSTRACT: Many epoxides and their precursors are high production volume chemicals that have major uses in the polymer industry and as intermediates in the manufacture of other chemicals. Several of these chemicals were demonstrated to be carcinogenic in laboratory animal studies conducted by the Ramazzini Foundation (e.g., vinyl chloride, acrylonitrile, styrene, styrene oxide, and benzene) and by the National Toxicology Program (e.g., ethylene oxide, 1,3-butadiene, isoprene, chloroprene, acrylonitrile, glycidol, and benzene). The most common sites of tumor induction were lung, liver, harderian gland, and circulatory system in mice; Zymbal's gland and brain in rats; and mammary gland and forestomach in both species. Differences in cancer outcome among studies of epoxide chemicals may be related to differences in study design (e.g., dose, duration, and route of exposure; observation period; animal strains), as well as biological factors affecting target organ dosimetry of the DNA-reactive epoxide (toxicokinetics) and tissue response (toxicodynamics). N7-Alkylguanine, N1-alkyladenine, and cyclic etheno adducts, as well as K-ras and p53 mutations, have been detected in animals and/or workers exposed to several of these chemicals. The classifications of these chemical carcinogens by IARC and NTP are based on animal and human data and results of mechanistic studies. Reducing occupational and environmental exposures to these chemicals will certainly reduce human cancer risks.
Annals of the New York Academy of Sciences 01/2003; 982:177-89. · 4.38 Impact Factor
[show abstract][hide abstract] ABSTRACT: A mathematical model was created to examine how xenobiotic ligands that bind to nuclear receptor proteins may affect transcriptional activation of hormone-regulated genes. The model included binding of the natural ligand (e.g. hormone) and xenobiotic ligands to the receptor, binding of the liganded receptor to receptor-specific DNA response sequences, binding of co-activator or co-repressor proteins (Rp) to the resulting complex, and the consequent transcriptional rate relative to that in the absence of the xenobiotic agent. The model predicted that the xenobiotic could act as a pure agonist, a pure antagonist, or a mixed agonist whose dose-response curve exhibits a local maximum. The response to the agent depends on the affinity of the liganded receptor-DNA complex for binding additional transcription factors (e.g. co-activator proteins). An inverted U-shaped dose-response occurred when basal levels of the natural ligand did not saturate receptor binding sites and the affinity for co-activator is weaker when the xenobiotic ligand is bound to the receptor than when the endogenous ligand is bound. The dose-response curve shape was not dependent on the affinity of the receptor for the xenobiotic agent; alteration of this value merely shifted the curve along the concentration axis. The amount of receptor, the density of DNA response sequences, and the affinity of the DNA-bound receptor for Rp determine the amplitude of the computed response with little overall change in curve shape. This model indicates that a non-monotonic dose-response is a plausible outcome for xenobiotic agents that activate nuclear receptors in the same manner as natural ligands.
Journal of Molecular Endocrinology 09/2002; 29(1):113-23. · 3.58 Impact Factor
[show abstract][hide abstract] ABSTRACT: A biologically based mathematical model was created to characterize time and dose-dependent relationships between exposure to nitrite and induction of methemoglobinemia. The model includes mass action equations for processes known to occur: oral absorption of nitrite, elimination from the plasma, partitioning between plasma and erythrocytes, binding of nitrite to hemoglobin and methemoglobin, and the free radical chain reaction for hemoglobin oxidation. The model also includes Michaelis-Menten kinetics for methemoglobin reductase-catalyzed regeneration of hemoglobin. Body weight-scaled rate constants for absorption (k(a)) and elimination (k(e)), the effective erythrocyte/plasma partition coefficient (P), and the apparent K(m) for methemoglobin reductase were the only parameters estimated by formal optimization to reproduce the observed time course data. Time courses of plasma nitrite concentrations and blood levels of hemoglobin and methemoglobin in male and female rats that had received single intravenous or oral doses of sodium nitrite were measured. Peak plasma levels of nitrite were achieved in both sexes approximately 30 min after oral exposure, and peak methemoglobin levels were achieved after 100 min. The model predicts that 10% of the hemoglobin is oxidized to the ferric form after oral doses of 15.9 mg/kg in male rats and 11.0 mg/kg in female rats and after intravenous doses of 8.9 and 7.1 mg/kg in male and female rats, respectively. The t(1/2) for recovery from methemoglobinemia was 60 to 120 min depending on dose and route of administration. A sensitivity analysis of the model was performed to identify to which parameters the predictions of the model were most sensitive and guide attempts to simplify the model. Replacement of the V(max) of methemoglobin reductase with a value representative of humans predicted a 10% methemoglobinemia following an intravenous dose of 5.8 mg/kg, in close agreement with an observed value of 5.7 mg/kg for humans.
Drug Metabolism and Disposition 07/2002; 30(6):676-83. · 3.36 Impact Factor
[show abstract][hide abstract] ABSTRACT: A diffusion limited physiologically based pharmacokinetic model for rats and mice was developed to characterize the absorption, distribution, metabolism, and elimination of naphthalene after inhalation exposure. This model includes compartments for arterial and venous blood, lung, liver, kidney, fat, and other organs. Primary sites for naphthalene metabolism to naphthalene oxide are the lung and the liver. The data used to create this model were generated from National Toxicology Program inhalation and iv studies on naphthalene and consisted of blood time-course data of the parent compound in both rats and mice. To examine the basis for possible interspecies differences in response to naphthalene, the model was extended to describe the distribution and metabolism of naphthalene oxide and the depletion and resynthesis of glutathione. After testing several alternative models, the one presented in this paper shows the best fit to the data with the fewest assumptions possible. The model indicates that tissue dosimetry of the parent compound alone does not explain why this chemical was carcinogenic to the female mouse lung but not to the rat lung. The species difference may be due to a combination of higher levels of naphthalene oxide in the mouse lung and a greater susceptibility of the mouse lung to epoxide-induced carcinogenesis. However, conclusions regarding which metabolite(s) may be responsible for the lung toxicity could not be reached.
Toxicology and Applied Pharmacology 11/2001; 176(2):81-91. · 3.98 Impact Factor
[show abstract][hide abstract] ABSTRACT: Criticisms of the scientific value of rodent carcinogenicity bioassays have focused on the arguments that the studies are too long and that most organ-specific carcinogenic effects observed in experimental animals have little or no relevance to humans. For example, Davies et al. (Davies, T.S., Lynch, B.S., Monro, A.M., Munro, I.C., Nestmann, E.R., 2000. Rodent carcinogenicity tests need be no longer than 18 months: an analysis based on 210 chemicals in the IARC Monographs. Food and Chemical Toxicology 38, 219-235) concluded that the duration of rodent bioassays should be no more than 18 months, based on their analysis of 210 International Agency for Research on Cancer (IARC) rodent carcinogens in which they report that most chemicals showed "tumorigenic effects" at or before 12 months. However, many of these "tumorigenic effects" reflect the occurrence of a single neoplasm, with most tumors occurring much later in the study. Reliance on a single tumor at an early time point as providing definitive evidence of rodent carcinogenicity is a dangerous practice that could produce both false positive and false negative outcomes. An extensive evaluation of the NTP database reveals that many rodent carcinogens produce later-appearing tumors that would not be detected as statistically significant in a 12-18 month study. Such a shortened duration study would be roughly equivalent to evaluating human cancer in subjects 30-50 years of age, which would result in markedly reduced study sensitivity. In fact, many investigators recommend extending the duration of rodent studies to 30 months or to a true lifetime to increase study sensitivity. We also do not agree with the second conclusion of Davies et al. (2000) that the mode of action of rodent carcinogenesis is sufficiently well understood to justify discounting the majority of organ-specific carcinogenic effects found in these studies. The consequences of performing rodent carcinogenicity studies with inadequate sensitivity, and then discounting most of the carcinogenic effects that are observed will be that potential human carcinogens will not be detected, thus forcing near total reliance on human studies for this purpose. This is not prudent public health policy.
Food and Chemical Toxicology 08/2001; 39(7):739-44. · 3.01 Impact Factor