The predictive value of pathological findings in animal toxicity studies.

Gopinath, C.

doi:10.1293/tox.8.89

Cited by 8 publications

(6 citation statements)

References 26 publications

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“…Additionally, an argument of differences in endocrinology between rat and human was also developed which would have particular weight in a regulatory toxicology and human risk extrapolation context. The argument of a difference in endocrine response between rat and human (Neumann, 1991;Gopinath, 1995;Gopinath, 1999) infers that the mechanism of tumourigenesis in the rat could not occur in humans. In this case, it revolved around prolactin being luteotrophic in rats, but not humans and this produced a unique hormonal milieu in the rat, allowing hormonal synergy/interactions that produced mammary tumours, but the same hormonal interactions did not occur in humans (Gopinath, 1999).…”

Section: Rodent Mammary Carcinogenesis and Prolactinmentioning

confidence: 99%

Adverse effects of prolactin in rodents and humans: breast and prostate cancer

2008

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Drugs and chemicals shown to induce mammary carcinogenesis in the rat/rodent via prolactin excess have traditionally been argued to pose little or no risk to humans in a regulatory toxicology context. The basis for this assumption is reviewed and placed into context with new evidence in humans that prolactin may be a tumour promoter in the breast and prostate. This evidence includes epidemiology, patient studies involving endocrine evaluation and molecular biology in human cells. It is concluded that hyperprolactinaemia is associated with an increase in breast cancer risk in both post and premenopausal women, that rat carcinogenicity studies are predictive of the human response, and that in a regulatory toxicology context prolactin-induced mammary tumours from nongenotoxic drugs and chemicals are an adverse effect that should not be ignored. More evidence is required concerning prostate cancer risk but molecular biology indicates that prolactin also induces prostate cell proliferation and inhibits apoptosis, which are similar to the responses observed in breast cancer cells.

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Section: Rodent Mammary Carcinogenesis and Prolactinmentioning

confidence: 99%

Adverse effects of prolactin in rodents and humans: breast and prostate cancer

2008

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“…For example, Gopinath (1999), noting that neuroleptics and other dopamine-inhibiting agents cause hyperprolactinaemia, clearly indicates that the occurrence of prolactin-mediated mammary tumours in rodents is a species-specific phenomenon; it is assumed that the compounds in question are non-genotoxic and Gopinath (1999) uses the term rodent, which is taken to mean rat and mouse (see below). The logic from Gopinath (1999) is that prolactin is luteotrophic in rodents but not humans, and a synergistic effect of the elevated prolactin (from dopamine-inhibiting compounds), progesterone (from the luteotrophic stimulatory action of prolactin on corpora lutea) and oestrogen on the mammary gland produces hyperplasia and tumours in rodents: because prolactin is not luteotrophic in humans (coupled with the lack of evidence that dopamine-inhibiting agents had any mammotrophic action in humans), the mechanism of prolactin-induced rodent mammary carcinogenesis was argued not to be relevant to humans (Neumann, 1991;Gopinath, 1995). Although most of the above reasoning has been based on work in the rat, there is clear evidence that prolactin is luteotrophic also in mice (Thordarson et al, 1997;Cargill et al, 1999) and that high prolactin is associated with the prevalence of mammary tumours at least in some strains of mouse (Wakefield et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Human relevance of rodent prolactin-induced non-genotoxic mammary carcinogenesis: prolactin involvement in human breast cancer and significance for toxicology risk assessments

Harvey

2005

J. Appl. Toxicol.

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Prolactin-induced mammary carcinogenesis in rodents, particularly rats, is often stated to be of low toxicological relevance to humans. This opinion appears to have developed from a number of lines of cited evidence. Firstly, there had been long experience of use of dopamine antagonists (that increase prolactin) in human medicine and no evidence of an increase in breast cancer incidence or risk had been reported. Secondly, dopamine agonists (that lower prolactin) had been shown to have no effect in human breast cancer treatment. Thirdly, the actions of prolactin were considered different between rodents and humans. However, recent evidence now suggests that prolactin has a major role in human breast cancer, and the similarity of mechanism with the rodent suggests that prolactin-mediated mammary carcinogenesis in rodents could be of much higher toxicological relevance to humans than previously thought. Large epidemiology studies have upgraded a limited database and shown that dopamine antagonists (both antipsychotics and anti-emetics) increase breast cancer risk, that hyperprolactinaemia is consistently associated with human breast cancer growth, development and poor prognosis, and that prolactin is indeed a mitogen in human breast cancer cells that suppresses apoptosis and upregulates BRCA1. It is now clear that initial studies giving dopamine agonists to breast cancer patients had no effect because breast cancer cells also produced prolactin independently of the pituitary, which remained uncontrolled and unrecognized in early clinical studies. The evidence for the role of prolactin in human breast cancer is now strong and consistent, and is discussed and related to the risk assessment of drugs and chemicals. The conclusion is that it is invalid to suggest that prolactin-induced mammary carcinogenesis in rodents is of low relevance to humans because prolactin can induce an adverse response in the mammary tissue of both rodents and humans alike. Drugs and chemicals causing rodent prolactin-induced mammary carcinogenesis may therefore pose a risk to humans via the same mechanism if exposures also increase prolactin secretion in humans.

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“…Nevertheless, one of the most critical issues on the extrapolation of animal data for carcinogenicity to human risk still remains elucidated. Rodents have been reported to be susceptible to neoplastic lesions in the kidney, urinary bladder, stomach, thyroid, mammary gland, uterus, testis, adrenal gland, liver, ovary and pancreatic island 46,47) and thus less relevant to human risk assessment in some cases. However, mode of action (MOA) approaches are needed to clarify the species specificity, except for α 2u -globulin-associated kidney tumors in male rats.…”

Section: Current Issues Test Methodsmentioning

confidence: 99%

Carcinogenicity Assessment for Risk Factors in Food:

Nishikawa

2013

Food Safety

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In the current carcinogenicity assessment, the threshold is a major issue for genotoxic carcinogens. Carcinogenicity is usually assessed in combination with genotoxicity data. The current assessment methodology is based on the hypothesis that non-genotoxic carcinogens have thresholds but genotoxic carcinogens do not. However, it remains unclear in most cases as to how much the detected genotoxic potential is actually associated with the carcinogenicity at an organ level. To clarify this critical issue, in vivo genotoxicity has been investigated in transgenic rodents carrying reporter genes, which can simultaneously detect both genotoxicity and carcinogenicity on each organ basis. Studies of a number of genotoxic carcinogens have revealed good correlations between in vivo genotoxicity and carcinogenicity. However, some discordant results have been also found in some cases. Besides experimentally observed values of genotoxicity, MOA or statistics might be taken into account for biological or practical threshold. Then, statistical or mathematical evaluation can provide values of BMDL or MOE even for strictly defined genotoxic carcinogens. Another major issue is concerning extrapolation of animal data for human risk. For this purpose, WOE approaches based on MOA may be extremely useful. Experiments using transgenic rodents such as p53, nrf2 or CAR knockout mice might be helpful to elucidate the mechanisms of carcinogenicity. The other issues concern the development of screening or alternative methods. In the future, in silico and in vitro approaches will be powerful tools for screening genotoxic and carcinogenic potentials of a number of chemicals/agents.

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The predictive value of pathological findings in animal toxicity studies.

Cited by 8 publications

References 26 publications

Adverse effects of prolactin in rodents and humans: breast and prostate cancer

Adverse effects of prolactin in rodents and humans: breast and prostate cancer

Human relevance of rodent prolactin-induced non-genotoxic mammary carcinogenesis: prolactin involvement in human breast cancer and significance for toxicology risk assessments

Carcinogenicity Assessment for Risk Factors in Food:

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