Screening for Chemical Contributions to Breast Cancer Risk: A Case Study for Chemical Safety Evaluation

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Abstract

Background

Current approaches to chemical screening, prioritization, and assessment are being reenvisioned, driven by innovations in chemical safety testing, new chemical regulations, and demand for information on human and environmental impacts of chemicals. To conceptualize these changes through the lens of a prevalent disease, the Breast Cancer and Chemicals Policy project convened an interdisciplinary expert panel to investigate methods for identifying chemicals that may increase breast cancer risk.

Methods

Based on a review of current evidence, the panel identified key biological processes whose perturbation may alter breast cancer risk. We identified corresponding assays to develop the Hazard Identification Approach for Breast Carcinogens (HIA-BC), a method for detecting chemicals that may raise breast cancer risk. Finally, we conducted a literature-based pilot test of the HIA-BC.

Results

The HIA-BC identifies assays capable of detecting alterations to biological processes relevant to breast cancer, including cellular and molecular events, tissue changes, and factors that alter susceptibility. In the pilot test of the HIA-BC, chemicals associated with breast cancer all demonstrated genotoxic or endocrine activity, but not necessarily both. Significant data gaps persist.

Conclusions

This approach could inform the development of toxicity testing that targets mechanisms relevant to breast cancer, providing a basis for identifying safer chemicals. The study identified important end points not currently evaluated by federal testing programs, including altered mammary gland development, Her2 activation, progesterone receptor activity, prolactin effects, and aspects of estrogen receptor β activity. This approach could be extended to identify the biological processes and screening methods relevant for other common diseases.

Citation

Schwarzman MR, Ackerman JM, Dairkee SH, Fenton SE, Johnson D, Navarro KM, Osborne G, Rudel RA, Solomon GM, Zeise L, Janssen S. 2015. Screening for chemical contributions to breast cancer risk: a case study for chemical safety evaluation. Environ Health Perspect 123:1255–1264; http://dx.doi.org/10.1289/ehp.1408337

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Most cited references 96

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(2004)

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The rodent estrous cycle: characterization of vaginal cytology and its utility in toxicological studies.

Ashley Murr, Sarah Cooper, Kenneth Goldman (2007)

While an evaluation of the estrous cycle in laboratory rodents can be a useful measure of the integrity of the hypothalamic-pituitary-ovarian reproductive axis, it can also serve as a way of insuring that animals exhibiting abnormal cycling patterns are disincluded from a study prior to exposure to a test compound. Assessment of vaginal cytology in regularly cycling animals also provides a means to establish a comparable endocrine milieu for animals at necropsy. The procedure for obtaining a vaginal smear is relatively non-invasive and is one to which animals can become readily accustomed. It requires few supplies, and with some experience the assessments can be easily performed in fresh, unstained smears, or in fixed, stained ones. When incorporated as an adjunct to other endpoint measures, a determination of a female's cycling status can contribute important information about the nature of a toxicant insult to the reproductive system. In doing so, it can help to integrate the data into a more comprehensive mechanistic portrait of the effect, and in terms of risk assessment, may provide some indication of a toxicant's impact on human reproductive physiology.

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In Vitro Screening of Environmental Chemicals for Targeted Testing Prioritization: The ToxCast Project

Richard S. Judson, Keith Houck, Robert J. Kavlock … (2009)

Background Chemical toxicity testing is being transformed by advances in biology and computer modeling, concerns over animal use, and the thousands of environmental chemicals lacking toxicity data. The U.S. Environmental Protection Agency’s ToxCast program aims to address these concerns by screening and prioritizing chemicals for potential human toxicity using in vitro assays and in silico approaches. Objectives This project aims to evaluate the use of in vitro assays for understanding the types of molecular and pathway perturbations caused by environmental chemicals and to build initial prioritization models of in vivo toxicity. Methods We tested 309 mostly pesticide active chemicals in 467 assays across nine technologies, including high-throughput cell-free assays and cell-based assays, in multiple human primary cells and cell lines plus rat primary hepatocytes. Both individual and composite scores for effects on genes and pathways were analyzed. Results Chemicals displayed a broad spectrum of activity at the molecular and pathway levels. We saw many expected interactions, including endocrine and xenobiotic metabolism enzyme activity. Chemicals ranged in promiscuity across pathways, from no activity to affecting dozens of pathways. We found a statistically significant inverse association between the number of pathways perturbed by a chemical at low in vitro concentrations and the lowest in vivo dose at which a chemical causes toxicity. We also found associations between a small set of in vitro assays and rodent liver lesion formation. Conclusions This approach promises to provide meaningful data on the thousands of untested environmental chemicals and to guide targeted testing of environmental contaminants.

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Author and article information

Journal

Journal ID (nlm-ta): Environ Health Perspect

Journal ID (iso-abbrev): Environ. Health Perspect

Journal ID (publisher-id): EHP

Title: Environmental Health Perspectives

Publisher: National Institute of Environmental Health Sciences

ISSN (Print): 0091-6765

ISSN (Electronic): 1552-9924

Publication date (Electronic): 02 June 2015

Publication date (Print): December 2015

Volume: 123

Issue: 12

Pages: 1255-1264

Affiliations

[1 ]Center for Occupational and Environmental Health, School of Public Health, University of California, Berkeley, Berkeley, California, USA

[2 ]Silent Spring Institute, Newton, Massachusetts, USA

[3 ]California Pacific Medical Center Research Institute, San Francisco, California, USA

[4 ]Division of the National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA

[5 ]Department of Nutritional Sciences and Toxicology, and

[6 ]Department of Environmental Health, University of California, Berkeley, Berkeley, California, USA

[7 ]California Environmental Protection Agency, Sacramento, California, USA

[8 ]Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Sacramento, California, USA

[9 ]Division of Occupational and Environmental Medicine, University of California, San Francisco, San Francisco, California, USA

[10 ]Natural Resources Defense Council (NRDC), San Francisco, California, USA

Author notes

Address correspondence to M.R. Schwarzman, 50 University Hall, #7360, Berkeley, CA 94720-7360 USA. Telephone: (510) 643-4685. E-mail: mschwarzman@ 123456berkeley.edu

Article

Publisher ID: ehp.1408337

DOI: 10.1289/ehp.1408337

PMC ID: 4671249

PubMed ID: 26032647

SO-VID: d40d1f97-7461-4a50-bd06-58364cefbd6c

License:

Publication of EHP lies in the public domain and is therefore without copyright. All text from EHP may be reprinted freely. Use of materials published in EHP should be acknowledged (for example, “Reproduced with permission from Environmental Health Perspectives”); pertinent reference information should be provided for the article from which the material was reproduced. Articles from EHP, especially the News section, may contain photographs or illustrations copyrighted by other commercial organizations or individuals that may not be used without obtaining prior approval from the holder of the copyright.

History

Date received : 26 February 2014

Date accepted : 20 May 2015

Date: 02 June 2015

Date: 01 December 2015

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Screening for Chemical Contributions to Breast Cancer Risk: A Case Study for Chemical Safety Evaluation

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Most cited references 96

Tobacco smoke and involuntary smoking.

The rodent estrous cycle: characterization of vaginal cytology and its utility in toxicological studies.

In Vitro Screening of Environmental Chemicals for Targeted Testing Prioritization: The ToxCast Project

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