Implications of multiple mechanisms of carcinogenesis for short‐term testing

Harper, Barbara; Morris, Debra L.

doi:10.1002/tcm.1770040604

Cited by 11 publications

(3 citation statements)

References 79 publications

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“…Organophosphate and carbamate pesticides have two possible mechanisms of carcinogenesis. One mechanism is based on genotoxicity (ability to react with DNA) and the other is based on epigenetic mechanisms (changes that alter genetic expression without modifying the DNA sequence) [50]. In vitro evidence indicates that organophosphate pesticides induce DNA mutations and methylation.…”

Section: Discussionmentioning

confidence: 99%

Brain cancer mortality in an agricultural and a metropolitan region of Rio de Janeiro, Brazil: a population-based, age-period-cohort study, 1996–2010

Filho

Koifman

et al. 2014

BMC Cancer

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BackgroundIndividuals who live in rural areas are at greater risk for brain cancer, and pesticide exposure may contribute to this increased risk. The aims of this research were to analyze the mortality trends and to estimate the age-period-cohort effects on mortality rates from brain cancer in two regions in Rio de Janeiro, Brazil.MethodsThis descriptive study examined brain cancer mortality patterns in individuals of both sexes, >19 years of age, who died between 1996 and 2010. They were residents of a rural (Serrana) or a non-rural (Metropolitan) area of Rio de Janeiro, Brazil. We estimated mortality trends using Joinpoint Regression analysis. Age-period-cohort models were estimated using Poisson regression analysis.ResultsThe estimated annual percentage change in mortality caused by brain cancer was 3.8% in the Serrana Region (95% confidence interval (CI): 0.8–5.6) and -0.2% (95% CI: -1.2–0.7) in the Metropolitan Region. The results indicated that the relative risk was higher in the rural region for the more recent birth cohorts (1954 and later). Compared with the reference birth cohort (1945–49, Serrana Region), the relative risk was four times higher for individuals born between 1985 and 1989.ConclusionsThe results of this study indicate that there is an increasing trend in brain cancer mortality rates in the rural Serrana Region in Brazil. A cohort effect occurred in the birth cohorts born in this rural area after 1954. At the ecological level, different environmental factors, especially the use of pesticides, may explain regional disparities in the mortality patterns from brain cancers.

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Section: Discussionmentioning

confidence: 99%

Brain cancer mortality in an agricultural and a metropolitan region of Rio de Janeiro, Brazil: a population-based, age-period-cohort study, 1996–2010

Filho

Koifman

et al. 2014

BMC Cancer

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“…Short-term tests mimic only a part of the phenomena that would occur in vivo (7). Cancer is now known to be a multifactorial, multistage, and multimechanistic disease in which many factors are relevant (8,9).…”

Section: Introductionmentioning

confidence: 99%

Multiple end point procedure to evaluate risk from pesticides.

Cantelli‐Forti

Paolini

Hrelia

1993

Environ Health Perspect

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Because of the potential environmental impact of pesticides and the large population potentially exposed, the effects of chronic exposure to pesticides need to be determined. Mutagenicity studies have been used to identify specific agents as potential carcinogens or other human health hazards. However, short-term tests are only theoretically correlated to carcinogenesis because their end points can measure only the genotoxic potential ofchemicals, i.e, their activities as initiating agents in multistep carcinogenesis. The objective of our research presented here is to provide a comprehensive examination of the mechanism of toxicity of a series of pesticides. These are substances for which toxicity, at both the genetic and metabolic level, has not been adequately described. Preliminary results on a broad series of compounds belonging to different biological classes (herbicide, insecticide, fungicide) seem to indicate that pesticides are toxic but are poor initiating agents, as shown by negative or weak positive results on different genetic end points (gene mutations, DNA effects, and chromosome aberrations in vitro and in vivo). Immunochemical and biochemical studies, however, seem to indicate the cocarcinogenic and promoting potential of these chemicals. As an example, the genotoxic and biochemical effects induced by Fenarimol (a fungicide) are discussed. The results reported stress the importance of identifying chemicals that act at different levels of the multistep carcinogenesis process to ascertain the risk associated with exposure.

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“…It is well recognized that no single assay is sufficient to predict either genetic damage or carcinogenicity, since both endpoints may be caused by multiple mechanisms (reviewed in Ref. 1). Thus, a number of batteries of separate tests have been suggested, usually including both in vivo and in vitro assays.…”

Section: Introductionmentioning

confidence: 99%

A combined testing protocol for assessing genotoxicity in individual animals: Application to environmental toxicology

et al. 1989

J of Applied Toxicology

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A multiple end-point approach to assessing genetic toxicity (the combined testing protocol, CTP) was evaluated in male and female CD-1 mice exposed subacutely (3 and 6 weeks) to low levels of a custom-blended gas mixture (epichlorohydrin, benzene, chloroprene and xylene, at 50, 100, 100, and 100 ppb, respectively, as the low dose, with concentration levels 10-fold and 100-fold higher as the intermediate and high doses, or 0.1, 1 and 10 ppm of benzene). Urine mutagenicity was tested in the Salmonella/microsome assay, chromosome aberrations were examined in bone marrow and spleen lymphocytes, micronuclei were measured in bone marrow and peripheral erythrocytes, and cytochrome P450 and glutathione S-transferases were measured in the liver. Structural aberrations in alveolar macrophages and spermatocytes, and thioguanine resistance in spleen lymphocytes were examined for their suitability for incorporation into the overall protocol. Spleen lymphocytes were the most sensitive indicator cells, and showed a dose-related increase (P less than 0.01) in structural chromosome aberrations and in cytotoxicity after 6 weeks of exposure. Analysis of micronucleus formation and metaphase aberrations in the bone marrow, and micronuclei in peripheral erythrocytes showed an overall statistically non-significant but positive trend at the high dose. No mutagenicity was detected in pooled urine samples. Liver microsomal cytochrome P450 was not increased, but cytosolic glutathione S-transferases were significantly increased in a dose-related manner. Since the probability of detecting a genotoxic effect increases with the number of endpoints and tissues examined, this approach should be applicable to many situations without having to perform separate experiments for each tissue examined.(ABSTRACT TRUNCATED AT 250 WORDS)

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Implications of multiple mechanisms of carcinogenesis for short‐term testing

Cited by 11 publications

References 79 publications

Brain cancer mortality in an agricultural and a metropolitan region of Rio de Janeiro, Brazil: a population-based, age-period-cohort study, 1996–2010

Brain cancer mortality in an agricultural and a metropolitan region of Rio de Janeiro, Brazil: a population-based, age-period-cohort study, 1996–2010

Multiple end point procedure to evaluate risk from pesticides.

A combined testing protocol for assessing genotoxicity in individual animals: Application to environmental toxicology

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