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The data indicates that any endocrine effects are secondary to germ cell changes and that boric acid or boric oxide does not bind directly to the estrogen receptor.

The structure of boric acid or boric oxide is fundamentally different from the multi-ringed chemical structures that are more often found to be estrogenic.

Based on this review of the scientific literature, the weight of the scientific evidence does not support the hypothesis that boric acid has a hormonal mechanism of action or an ability to cause toxicity through endocrine disruption. An endocrine disruptor is an exogenous substance that causes adverse health effects secondary to changes in endocrine function. While it is clear that high doses of boric acid can produce male reproductive toxicity and developmental toxicity in laboratory animals, there is no convincing evidence that boric acid-induced health effects are secondary to changes in endocrine function.

Additional information

Boric acid does not exhibit the properties or characteristics of hormones, including estrogens and androgens. Several studies have evaluated possible endocrine effects of boron compounds (Wang et al., 2008; Sauls et al., 1992; Anderson et al., 1992; Fail et al., 1992, Fail et al., 1991; Treinen & Chapin, 1991; Linder et al., 1990; Grizzle et al., 1989; Lee et al., 1978). The data indicates that any endocrine effects are secondary to germ cell changes since histologic changes occurred by Day 7 while peripheral hormone changes were not detected before Day 14 of treatment (Fail et al. 1998). Boric acid-induced testicular toxicity in rodents appears to be due to a direct effect on Sertoli cells (not an effect on the endocrine system). Boric acid was not carcinogenic in either mice (NTP, 1987) or rats (Weir and Fisher, 1972); endocrine-disrupting substances typically produce hormonally-related tumors in chronic toxicity studies in animals. Boric acid was negative in a yeast two-hybrid estrogenicity assay, indicating that boric acid does not bind directly to the estrogen receptor and mimic endogenous estrogen (Nishihara et al 2000). The structure of boric acid is fundamentally different from the multi-ringed chemical structures that are more often found to be estrogenic. Boric acid may be too small molecularly to interact with the estrogen receptor or other steroid hormone receptors. Conflicting evidence of estrogenic activity was observed in a battery of short-term in vitro and in vivo studies (Wang et al., 2008). For example, an increase in “organ coefficient of uterus” (wet uterine weight/body weight) was observed at the high dose in ovariectomized rats administered boric acid (Wang et al., 2008); however, uterine and body weights were not reported, and a dose-response relationship was not demonstrated. In comparison, boric acid did not stimulate the proliferation of MCF-7 human breast cancer cells (Wang et al., 2008).

No evidence of hormonally-related clinical symptoms have been reported in workers exposed to boric acid (Whorton et al., 1994; Sayli et al., 1998; Scialli et al., 2010; Robbins et al., 2010). An increase in the serum concentrations of both 17b-estradiol and testosterone were reported in postmenopausal women given a daily boron supplement (3 mg B/day) following 119 days on a boron-deficient diet; the elevation appeared more marked when dietary magnesium was low (Nielsen et al., 1987; Nielsen, 1994). In contrast,decreasesin serum 17b-estradiol and progesterone were reported in another study of postmenopausal women given 3.25 mg/B in the diet when dietary magnesium was low compared to postmenopausal women receiving a boron-deficient diet (Nielsen, 2004). In a NASA study of young male bodybuilders, boron supplementation had no effect on blood testosterone levels or lean body mass (Green and Ferrando, 1994). 

Epidemiological, animal, and cell culture studies have identified boric acid as a chemopreventative agent in prostate cancer (Cui et al., 2004;Barranco and Eckhert, 2004; Barranco and Eckhert, 2006; Barranco et al., 2007; Barranco et al., 2009; Henderson et al., 2009).   Although estrogens are frequently used to treat prostate cancer, the chemopreventative effects of boric acid on prostate cancer appear to have a non-endocrine mode of action. It was recently demonstrated in human prostate cancer cells that boron causes a dose dependent decrease of Ca(2+) release from ryanodine receptor sensitive stores, suggesting that higher boric acid blood levels lower the risk of prostate cancer by reducing intracellular Ca(2+) signals and storage (Henderson et al., 2009). Similarly, Barranco et al. (2009) hypothesized that the toxicity of boric acid in human prostate cancer cells stems from the ability of high concentrations to impair Ca2+ signaling.

Focusing on estrogen, androgen, and thyroid pathways, the U.S. Environmental Protection Agency (EPA) ToxCast program defined putative endocrine profiles and derived a relative rank or score for the entire ToxCast library of 309 unique chemicals. Effects on other nuclear receptors and xenobiotic metabolizing enzymes were also considered, as were pertinent chemical descriptors and pathways relevant to endocrine-mediated signaling. Combining multiple data sources into an overall, weight-of-evidence Toxicological Priority Index (ToxPi) score for prioritizing further chemical testing resulted in more robust con­clusions than any single data source taken alone. The range of possible ToxPi scores was 0 to 6, with higher scores indicating greater potential of endocrine-related toxicity. Boric acid received a ToxPi score of 0.117 (Reif et al. 2010), the lowest score of the 309 chemicals evaluated. The low ToxPi score for boric acid indicates low potential endocrine-related toxicity.

 

As part of the Endocrine Disruptor Screening Program (EDSP), the U.S. EPA used high-throughput and computational methods to evaluate the endocrine bioactivity of environmental chemicals. Boric Acid was one of 1812 chemicals evaluated that include 387 pesticide active ingredients, and 364 pesticide inerts with most of the remaining chemicals relevant to the EDSP, contingent on potential for exposure of substantial human populations through sources of drinking water. Results from 18 estrogen receptor (ER) ToxCast high-throughput screening assays were integrated into a computational model. Model scores range from 0 (no activity) to 1 (bioactivity of 17β-estradiol). The suite of high throughput assays measure the molecular initiating event (i.e., receptor binding), in addition to several key events (e.g., receptor dimerization, DNA binding, transactivation, gene expression, and cell proliferation) in an adverse outcome pathway. In the future EPA plans to use this approach for validating new computational tools to screen for androgen and thyroid effects. Boric acid score was 0 (Browne et al. 2015). Further evidence boric acid is not an endocrine active substance.

 

The potential reproductive and endocrine toxicity of boric acid (BA) in the African clawed frog, Xenopus laevis, was evaluated following a modified Amphibian Growth and Reproduction Assay (AGRA) model consisting of a 30-d exposure of adult frogs (Fort 2015). Endocrine endpoints included plasma estradiol (E2), testosterone (T), dihydrotestosteone (DHT), gonadal CYP 19 (aromatase), and gonadal5α-reductase (5-AR). No effects on endocrine endpoints were observed. As expected, although exposure to boric acid altered reproductive endpoints at the high dose in both male and female frogs, there was no adverse impact on the endocrine endpoints. These results confirm that although boric acid is capable of inducing reproductive toxicity at high concentrations, it is not an endocrine disrupting agent.