What are metalloestrogens?

Metalloestrogens are metals that activate estrogen receptors in the absence of estradiol, potentially contributing to aberrant estrogen signaling within breast tissue.[7]  In 2003, Martin et al. demonstrated that several metals including cadmium, copper, cobalt, nickel, lead, mercury, tin, and chromium can activate estrogen receptor-α (ERα) in MCF-7 breast cancer cells, leading to 2-5 fold increases in cell proliferation. This seminal work established the concept of “metalloestrogens” – metals that mimic estrogen activity.[2]

Recent studies have increasingly focused on joint exposures to multiple metals. The EPIC-Spain cohort study (2024) found positive associations between breast cancer risk and concentrations of aluminum, arsenic, nickel, cadmium, and lead, while cobalt showed an inverse association.[6] 

Cadmium

Cadmium naturally occurs in the Earth’s crust and is found in materials extracted from the earth, including metals such as zinc, lead and iron, and fossil fuels such as coal, oil and natural gas. Most cadmium produced today comes from zinc mining and refining, and from recycled nickel-cadmium batteries. Cadmium is used in batteries, photocopying, mirrors, vacuum tubes, lubricants, fungicides, glass coloring, paint and nuclear reactors, and can also be found in smoke detectors and Teflon-containing cooking materials.

Arsenic

Arsenic is a natural element found in rocks, soil, water, air, and in plants and animals. People are exposed through both natural sources and human activities. Inorganic arsenic compounds, which are more toxic and linked to cancer, are found in industry, building products, and arsenic-contaminated water.[8] The highest levels of arsenic in foods are found in seafood, rice, rice products, mushrooms, and poultry.

Lead

Lead is a naturally occurring metal that has been widely used in various industrial applications. Common sources of exposure include lead-based paints, contaminated soil and dust, certain consumer products, and occupational settings. Lead has no known physiological function in humans and is classified among the nonessential metals.[9]

Nickel

Nickel is both an essential trace element and a widespread environmental contaminant. It is used extensively in metallurgy, electroplating, and manufacturing of stainless steel, coins, and batteries. Occupational exposure occurs primarily in refining, welding, and electroplating industries.[10]

Antimony

Antimony is a metalloid element used in flame retardants, batteries, ceramics, glass, and plastics. Dietary exposure is typically the primary source for the general population, with antimony being the metalloestrogen to which people are least exposed, with median daily dietary intake estimated at approximately 2 μg/day.[11]

What evidence links heavy metals to breast cancer?

Tissue and Blood Studies

Researchers have found significantly higher concentrations of multiple metals, including nickel, chromium, zinc, mercury, lead and cadmium, in cancerous breast tissue compared with noncancerous tissue.[12] Blood serum samples from women diagnosed with breast cancer also showed elevated concentrations of many of these same metals.[13] Higher cadmium levels in both urine[14] and blood[15] have been associated with increased breast cancer risk.

Dietary Studies

A statistically significant relationship has been found between dietary consumption of cadmium and later diagnosis of uterine cancers[16] and post-menopausal breast cancers.[17] A prospective study following women for 22 years found that higher dietary intake of cadmium was associated with increased breast cancer risk, with effects being more pronounced for women who had been premenopausal at the beginning of the study.[18]

A large prospective study using toenail biomarkers to assess exposure to 15 metals found limited evidence supporting individual metals as breast cancer risk factors, though molybdenum was associated with reduced breast cancer risk.[9]

Environmental and Occupational Studies

Higher airborne levels of cadmium, mercury and lead have been associated with increased risk of developing post-menopausal breast cancer.[19] Occupational exposure studies have shown mixed results, with some suggesting increased breast cancer risk among women exposed to cadmium in metal plating and coating industries.[20]

Laboratory Studies and Mechanisms

Laboratory studies have demonstrated that multiple metals including copper, cobalt, nickel, lead, mercury, chromium and cadmium act like the hormone estrogen by increasing cell proliferation of breast cancer cells in vitro.[21],[22] Cadmium has been shown to possess the highest level of estrogenic activity among tested metals.[5]

Arsenic-Specific Mechanisms

Arsenic exposure has been shown to induce functional re-expression of estrogen receptor α by demethylation of DNA in estrogen receptor-negative human breast cancer cells.[23] Chronic arsenic exposure to breast epithelial cells resulted in acquired cancer cell phenotype through overexpression of aromatase, thereby activating oncogenic processes independent of estrogen receptors.[24] Studies show arsenic can transform breast epithelia through aromatase activation, leading to increased estrogen synthesis and cancer cell characteristics.

Effects in Animal Studies

In animal trials, low doses of cadmium led to increased branching and bud formation in mammary tissue, and offspring of rats exposed to cadmium experienced early onset of puberty—both factors known to increase breast cancer risk later in life.[25] Metalloestrogen exposure has been associated with alterations in breast anatomy including early onset of puberty, increased epithelial area, and increased number of terminal end buds in mammary glands.[26]

What about effects of exposure to cadmium in women who have been diagnosed with breast cancer?

For women living with a breast cancer diagnosis, higher blood cadmium levels have been associated with earlier distant organ metastases.[27] This suggests that metal exposure may not only contribute to cancer development but also influence cancer progression and outcomes.

Who is most likely to be exposed to cadmium?

High-Risk Occupations

An estimated 300,000 workers are exposed to cadmium in the United States alone, primarily in manufacturing and construction industries, as well as the expanding nickel-cadmium battery recycling industry. The main industries of concern include metal smelting and refining, battery production, plastics manufacturing, coatings production, and solar panel manufacturing.[28]

Vulnerable Populations

• Consumers of high-risk foods: Those who regularly consume shellfish, grains, leafy vegetables, and liver and kidney meats face higher dietary exposure to multiple metals
• Women of reproductive age and menopausal women: Most vulnerable to metals that mimic estradiol due to ongoing hormonal fluctuations[29]
• Pregnant women and fetuses: Metals can transfer through the placenta, making fetuses especially vulnerable[30]
• Children: Particularly susceptible as heavy metals accumulate in the body over time[31]
• Smokers: Tobacco smoke contains multiple metals including cadmium, and because only small fractions of inhaled metals leave the body, concentrations build up over time

Who is most vulnerable to the health effects?

Women in their reproductive years and menopausal women are most vulnerable to metals that mimic estradiol.[25] Fetuses are especially vulnerable to the effects of cadmium as it can be transferred through the placenta.[26]  Children are also vulnerable as heavy metals build up in the body over time.[27]

What are the top tips to avoid exposure?

Occupational Protection

• Wear appropriate personal protective equipment, including protective clothing and breathing masks, when working in metal, plastic, or waste management fields
• Follow workplace safety protocols for handling metal-containing materials
• Ensure proper ventilation in work environments with potential metal exposure

Consumer Choices

• Avoid nickel-cadmium batteries and dispose of them safely through appropriate recycling programs
• Be mindful of food choices, particularly limiting high-arsenic foods like certain rice products
• Consider the source of drinking water, especially in areas known for high natural arsenic content
• Limit use of products containing metalloestrogens when alternatives are available

Dietary Considerations

• Diversify food sources to avoid excessive exposure from any single contaminated source
• Be aware that rice and rice products may contain higher levels of arsenic
• Consider the potential for metal contamination in seafood from polluted waters

Current Research Gaps and Future Directions

While evidence suggests associations between metalloestrogen exposure and breast cancer risk, more research is needed to:

• Establish definitive causal relationships through large-scale prospective studies
• Better understand the effects of metal mixtures rather than individual metals
• Investigate critical windows of exposure (prenatal, puberty, postmenopausal periods)
• Develop biomarkers for better exposure assessment
• Evaluate interventions to reduce population exposure

The complex interactions between multiple metals, their combined estrogenic effects, and individual susceptibility factors require further investigation to fully understand their role in breast cancer etiology.

Updated 2025