US EPA's regulatory pesticide evaluations need clearer guidelines for considering mammary gland tumors and other mammary gland effects

Cardona, Bethsaida; Rudel, Ruthann A.

doi:10.1016/j.mce.2020.110927

Cited by 22 publications

(25 citation statements)

References 35 publications

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“…Chemicals not included in any of these sources were classified as having inadequate evidence to classify. We also noted whether any of the chemicals had been listed as having observed mammary tumors in pesticide U.S. EPA Reregistration Eligibility Documents (Cardona and Rudel 2020).…”

Section: In Vivo End Points and Chemical Cancer Risk Assessmentmentioning

confidence: 99%

“…We also used existing reviews of chemicals with mammary gland effects to determine the frequency of effects on E2 and P4 synthesis among these chemicals. We reviewed how many of the ∼ 250 mammary carcinogens or mammary gland developmental disruptors listed in three review articles published by this team (Cardona and Rudel 2020;Rudel et al 2007Rudel et al , 2011 were also tested in the HT-H295R assay, and if so, whether they increased E2 or P4.…”

Section: In Vivo End Points and Chemical Cancer Risk Assessmentmentioning

confidence: 99%

“…In addition, this research team previously compiled ∼ 250 chemicals with reported mammary gland tumors or other mammary gland effects, such as altered mammary gland development (Cardona and Rudel 2020;Rudel et al 2007Rudel et al , 2011. For some of these chemicals, although mammary effects were reported, they were also dismissed as not treatment related (Cardona and Rudel 2020).…”

Section: Carcinogenicity Reproductive and Developmental Toxicity Findingsmentioning

confidence: 99%

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Application of an in Vitro Assay to Identify Chemicals That Increase Estradiol and Progesterone Synthesis and Are Potential Breast Cancer Risk Factors

Cardona

Rudel

2021

Environ Health Perspect

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BACKGROUND: Established breast cancer risk factors, such as hormone replacement therapy and reproductive history, are thought to act by increasing estrogen and progesterone (P4) activity. OBJECTIVE: We aimed to use in vitro screening data to identify chemicals that increase the synthesis of estradiol (E2) or P4 and evaluate potential risks. METHOD: Using data from a high-throughput (HT) in vitro steroidogenesis assay developed for the U.S. Environmental Protection Agency (EPA) ToxCast program, we identified chemicals that increased estradiol (E2-up) or progesterone (P4-up) in human H295R adrenocortical carcinoma cells. We prioritized chemicals by their activity. We compiled in vivo studies and assessments about carcinogenicity and reproductive/developmental (repro/dev) toxicity. We identified exposure sources and predicted intakes from the U.S. EPA's ExpoCast. RESULTS: We found 296 chemicals increased E2 (182) or P4 (185), with 71 chemicals increasing both. In vivo data often showed effects consistent with this mechanism. Of the E2-and P4-up chemicals, about 30% were likely repro/dev toxicants or carcinogens, whereas only 5-13% were classified as unlikely. However, most of the chemicals had insufficient in vivo data to evaluate their effects. Of 45 chemicals associated with mammary gland effects, and also tested in the H294R assay, 29 increased E2 or P4, including the well-known mammary carcinogen 7,12-dimethylbenz(a)anthracene. E2-and P4-up chemicals include pesticides, consumer product ingredients, food additives, and drinking water contaminants. DISCUSSION: The U.S. EPA's in vitro screening data identified several hundred chemicals that should be considered as potential risk factors for breast cancer because they increased E2 or P4 synthesis. In vitro data is a helpful addition to current toxicity assessments, which are not sensitive to mammary gland effects. Relevant effects on the mammary gland are often not noticed or are dismissed, including for 2,4-dichlorophenol and cyfluthrin. Fifty-three active E2-up and 59 active P4-up chemicals that are in consumer products, food, pesticides, or drugs have not been evaluated for carcinogenic potential and are priorities for study and exposure reduction.

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Section: In Vivo End Points and Chemical Cancer Risk Assessmentmentioning

confidence: 99%

Section: In Vivo End Points and Chemical Cancer Risk Assessmentmentioning

confidence: 99%

Section: Carcinogenicity Reproductive and Developmental Toxicity Findingsmentioning

confidence: 99%

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Application of an in Vitro Assay to Identify Chemicals That Increase Estradiol and Progesterone Synthesis and Are Potential Breast Cancer Risk Factors

Cardona

Rudel

2021

Environ Health Perspect

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“…A mixture of DDT and permethrin results in disruption of homeostatic function in hepatocytes, and at high levels, results in inflammation and oxidative stress [6]. The benign status of commonly used pesticides is being challenged [7][8][9], but the regulatory agencies have not responded by updating guidelines and policies [2].…”

Section: Introductionmentioning

confidence: 99%

Epigenome-wide association study for pesticide (Permethrin and DEET) induced DNA methylation epimutation biomarkers for specific transgenerational disease

et al. 2020

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Background Permethrin and N,N-diethyl-meta-toluamide (DEET) are the pesticides and insect repellent most commonly used by humans. These pesticides have been shown to promote the epigenetic transgenerational inheritance of disease in rats. The current study was designed as an epigenome-wide association study (EWAS) to identify potential sperm DNA methylation epimutation biomarkers for specific transgenerational disease. Methods Outbred Sprague Dawley gestating female rats (F0) were transiently exposed during fetal gonadal sex determination to the pesticide combination including Permethrin and DEET. The F3 generation great-grand offspring within the pesticide lineage were aged to 1 year. The transgenerational adult male rat sperm were collected from individuals with single and multiple diseases and compared to non-diseased animals to identify differential DNA methylation regions (DMRs) as biomarkers for specific transgenerational disease. Results The exposure of gestating female rats to a permethrin and DEET pesticide combination promoted transgenerational testis disease, prostate disease, kidney disease, and the presence of multiple disease in the subsequent F3 generation great-grand offspring. The disease DMRs were found to be disease specific with negligible overlap between different diseases. The genomic features of CpG density, DMR length, and chromosomal locations of the disease specific DMRs were investigated. Interestingly, the majority of the disease specific sperm DMR associated genes have been previously found to be linked to relevant disease specific genes. Conclusions Observations demonstrate the EWAS approach identified disease specific biomarkers that can be potentially used to assess transgenerational disease susceptibility and facilitate the clinical management of environmentally induced pathology.

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“…Pollution negatively affects every aspect of physical and mental human health including intellectual ability [ 1 – 3 ]. Many commonly used pesticides have endocrine-disrupting and cancer-inducing effect [ 4 ]. Pathogenic microbes specifically infectious microorganisms are always a challenge to human survival.…”

Section: Introductionmentioning

confidence: 99%

Application of DNA-Nanosensor for Environmental Monitoring: Recent Advances and Perspectives

Kumar

Guleria

2020

Curr Pollution Rep

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US EPA's regulatory pesticide evaluations need clearer guidelines for considering mammary gland tumors and other mammary gland effects

Cited by 22 publications

References 35 publications

Application of an in Vitro Assay to Identify Chemicals That Increase Estradiol and Progesterone Synthesis and Are Potential Breast Cancer Risk Factors

Application of an in Vitro Assay to Identify Chemicals That Increase Estradiol and Progesterone Synthesis and Are Potential Breast Cancer Risk Factors

Epigenome-wide association study for pesticide (Permethrin and DEET) induced DNA methylation epimutation biomarkers for specific transgenerational disease

Application of DNA-Nanosensor for Environmental Monitoring: Recent Advances and Perspectives

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