The human relevance framework (HRF) outlines a four-part process, beginning with data on the mode of action (MOA) in laboratory animals, for evaluating the human relevance of animal tumors. Drawing on U.S. EPA and IPCS proposals for animal MOA analysis, the HRF expands those analyses to include a systematic evaluation of comparability, or lack of comparability, between the postulated animal MOA and related information from human data sources. The HRF evolved through a series of case studies representing several different MOAs. HRF analyses produced divergent outcomes, some leading to complete risk assessment and others discontinuing the process, according to the data available from animal and human sources. Two case examples call for complete risk assessments. One is the default: When data are insufficient to confidently postulate a MOA for test animals, the animal tumor data are presumed to be relevant for risk assessment and a complete risk assessment is necessary. The other is the product of a data-based finding that the animal MOA is relevant to humans. For the specific MOA and endpoint combinations studied for this article, full risk assessments are necessary for potentially relevant MOAs involving cytotoxicity and cell proliferation in animals and humans (Case Study 6, chloroform) and formation of urinary-tract calculi (Case Study 7, melamine). In other circumstances, when data-based findings for the chemical and endpoint combination studied indicate that the tumor-related animal MOA is unlikely to have a human counterpart, there is little reason to continue the risk assessment for that combination. Similarly, when qualitative considerations identify MOAs specific to the test species or quantitative considerations indicate that the animal MOA is unlikely to occur in humans, such hazard findings are generally conclusive and further risk assessment is not necessary for the endpoint-MOA combination under study. Case examples include a tumor-related protein specific to test animals (Case Study 3, d-limonene), the tumor consequences of hormone suppression typical of laboratory animals but not humans (Case Study 4, atrazine), and chemical-related enhanced hormone clearance rates in animals relative to humans (Case Study 5, phenobarbital). The human relevance analysis is highly specific for the chemical-MOA-tissue-endpoint combination under analysis in any particular case: different tissues, different endpoints, or alternative MOAs for a given chemical may result in different human relevance findings. By providing a systematic approach to using MOA data, the HRF offers a new tool for the scientific community's overall effort to enhance the predictive power, reliability and transparency of cancer risk assessment.

A framework for human relevance analysis of information on carcinogenic modes of action.

http://www.hormonebalance.org/images/documents/Liao%2002%20Role%20of%20Androgens%20BCa%20Dose%20SB&MB.pdf

Roles of androgens in the development, growth, and carcinogenesis of the mammary gland.

The aim of this study was to investigate the effect of fetal exposure to diethylstilbestrol (DES) on the induction of mammary tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) in female rats. Pregnant rats were fed only normal diet, diet mixed with 0.1 ppm DES throughout pregnancy period or diet mixed with 0.1, 1 or 10 ppm DES from day 13 of pregnancy till the end of pregnancy. Delivered pups were given 10 mg DMBA by gastric intubation at 50 days after birth and observed till 336 days after birth. Some rats exposed to DES throughout pregnancy and those from day 13 till the end of pregnancy showed endocrine disrupting effects such as absence of CL and active lactation in mammary glands at necropsy, while no abnormal estrus cycle such as persistent estrus was seen during the observation period until 88 days after birth. Fetal exposure to 0.1 ppm DES throughout pregnancy period, 0.1 and 1 ppm DES from day 13 of pregnancy increased the incidence and number of mammary carcinomas (MCs) at the earlier period while exposure to 0.1 ppm DES throughout pregnancy period enhanced the incidence and number of benign proliferative lesions (PLs) at the later period. MCs appeared earlier than benign PLs. These results suggest that exposure to DES throughout pregnancy and from day 13 of pregnancy could induce endocrine disrupting conditions and enhance the induction of MCs and that exposure to DES throughout pregnancy enhance PLs.

Effects of Fetal Exposure to Diethylstilbestrol on Mammary Tumorigenesis in Rats

The aim of this study was to investigate the effects of neonatal administration of a relatively high dose of diethylstilbestrol (DES) on the induction of mammary carcinomas (MCs) and benign proliferative lesions (PLs) induced by 7,12-dimethylbenz[a]anthracene (DMBA) in female rats. Three different terms of daily administration of DES (10 microg) were used: 0-14, 0-5, and 6-14 days after birth. Control animals were administered solvent (oil) alone once daily from 0 to 14 days after birth. Rats were given DMBA (10 mg) at 50 days after birth. All rats administered DES showed persistent estrus and anovulatory ovaries. In rats administered DES from 0 to 14 and 0 to 5 days after birth there was protection from development of MCs and PLs, and serum levels of both estrogen and progesterone were significantly lower than in the control animals at 100 days after birth. In rats administered DES from 6 to 14 days after birth, the incidence of MCs was equal to that of the control animals (100%), and the number of PLs was significantly higher than in the control animals. The critical period for exposure to endocrine disruptors, such as DES, affecting the induction of MCs and PLs may be from 0 to 5 days after birth.

https://journals.sagepub.com/doi/pdf/10.1354/vp.46-1-142

Effects of neonatally administered high-dose diethylstilbestrol on the induction of mammary tumors induced by 7,12-dimethylbenz[a]anthracene in female rats.

In order to determine the influence of strain and sex on local carcinogenesis in rat mammary tissue, 1 mg of 7, 12 dimethylbenz(a)anthracene (DMBA) was dusted directly onto the exposed mammary gland of 30-day-old Long-Evans (L-E) rats and Sprague-Dawley (S-D) rats. The experiment was terminated 28 weeks after application of the carcinogen. Tumors measuring between 1 and 2 cm in diameter were harvested from female L-E rats with high frequency (85%) and long latency (mean: 23.7 weeks after DMBA dusting), and from female S-D rats with extremely high frequency (98%) and short latency (16.7 weeks). Male rats of both strains were almost identically much less susceptible to DMBA (L-E; 55%, 25.0 weeks, S-D; 53%, 23.9 weeks). Ovariectomized S-D (47%, 24.9 weeks) and orchiectomized S-D (30%, 24.8 weeks) rats, which were gonadectomized at 30 days of age, respectively, were also much less susceptible. A variety of histologies, mostly malignant epithelial, mesenchymal or mixed tumors, were noted in each group. The carcinomatous response in the mammary tissue was much higher in female S-D (96%) than in female L-E (50%) rats, and very low in male and gonadectomized rats (10-20%). In contrast, the sar-comatous response in the mammary tissue was moderate in female and male L-E and male S-D (43-50%) rats, and low in the other groups (15-29%). Acta Pathol Jpn 40: 9–13, 1990.

Influence of strain and sex on the local development of mammary tumors induced by direct application of DMBA powder to rat mammary glands.

Biweekly intragastric intubations of 7,12-dimethylbenz[a]anthracene (DMBA) rapidly induce mammary carcinoma in high yield in gonadectomized female and male rats. These tumors are ovary-independent, though they contain estrogen receptors (ER). In 84.4% of 32 female rats and in 100% of 35 male rats which were gonadectomized at 27 days of age and given 10 mg of DMBA 8 times at 14-day intervals starting from 28 days of age, mammary carcinoma developed 102.4 +/- 28.1 (SD) and 107.2 +/- 25.5 (SD) days, respectively, after the first intubation of DMBA. More than 55% (55 approximately 83%) of seed tumors taken from 18 tumors induced in ovariectomized rats and 18 tumors induced in orchiectomized rats could grow in intact and ovariectomized females and intact and castrated males. Cytosol ER were found in all of 10 tumors induced in gonadectomized male and female rats.

Mammary Carcinoma Induced by a Series of Intragastric Intubations of 7,12-Dimethylbenz〔a〕Anthracene in Gonadectomized Female and Male Sprague-Dawley Rats

Matsumoto K

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Mammary Carcinoma Induced by a Series of Intragastric Intubations of 7,12-Dimethylbenz〔a〕Anthracene in Gonadectomized Female and Male Sprague-Dawley Rats