What can we learn from epidemiological studies on chronic boron exposure?

Boric acid and sodium borates are classified as toxic to reproduction and development under category 1B, with the hazard statement of H360FD (May damage fertility. May damage the unborn child) in the EU-CLP regulation. This classification triggered environmental and occupational epidemiology studies on boron in China, Türkiye, and Argentina. The highest mean total daily boron exposure (DBE) levels in mining areas or processing plants in China and Türkiye were 41.2 and 47.17 mg/day, respectively. These DBE levels are higher than the proposed reference doses (RfDs) for the developmental (9.6 mg B/day) and reproductive effects (20.3 mg B/day) of boron in females and males. Despite these high exposure levels in occupational settings, boron-mediated reproductive and developmental effects have not been reported. Blood (or serum) boron concentrations were also reported in these studies. The highest mean blood-boron concentration reported for the boron-exposed male workers in Türkiye is 570.6 ng B/g (ppb). This blood-boron concentration is still much lower than the blood boron concentrations corresponding to the no observed adverse effect level (NOAEL) for both developmental and reproductive effects in rats. Given the blood boron concentrations reported in current epidemiological studies, the lack of reproductive and developmental effects in humans is not surprising. Recent epidemiological studies have proven that it will not be possible to reach the critical blood boron concentrations in humans for the reproductive and developmental effects, especially in daily life.

The role of endogenous versus exogenous sources in the exposome of putative genotoxins and consequences for risk assessment.

The "totality" of the human exposure is conceived to encompass life-associated endogenous and exogenous aggregate exposures. Process-related contaminants (PRCs) are not only formed in foods by heat processing, but also occur endogenously in the organism as physiological components of energy metabolism, potentially also generated by the human microbiome. To arrive at a comprehensive risk assessment, it is necessary to understand the contribution of in vivo background occurrence as compared to the ingestion from exogenous sources. Hence, this review provides an overview of the knowledge on the contribution of endogenous exposure to the overall exposure to putative genotoxic food contaminants, namely ethanol, acetaldehyde, formaldehyde, acrylamide, acrolein, α,ß-unsaturated alkenals, glycation compounds, N-nitroso compounds, ethylene oxide, furans, 2- and 3-MCPD, and glycidyl esters. The evidence discussed herein allows to conclude that endogenous formation of some contaminants appears to contribute substantially to the exposome. This is of critical importance for risk assessment in the cases where endogenous exposure is suspected to outweigh the exogenous one (e.g. formaldehyde and acrolein).

Evaluation of oxidative stress and immune parameters of boron exposed males and females.

There is growing evidence that boron (B) and B compounds are essential nutrients for animals and humans. Besides, B compounds have been suggested to treat inflammation and oxidative stress. As a part of our "Boron Project II" on B-exposed persons in Bandirma and Bigadic (Turkey) between 2014 and 2017, anti-oxidant/pro-oxidant and inflammatory parameters were assessed. In this first large-scale human study biomarkers of oxidative stress such as the enzyme activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and the levels of malondialdehyde (MDA), glutathione (GSH) and 8-hydroxy-2'-deoxy-guanosine (8-OH-dG) were investigated, in relation to B exposure. The immune biomarkers interleukin (IL)-1ra, IL-6, IL-8 and nuclear factor kappa B (NF-κB) levels were included. There was no influence of human exposure to B on the parameters of oxidative stress and inflammation.

Effects of boron compounds on human reproduction.

Because of the high pKa of boric acid, inorganic borates, when taken up by the human or animal organism, exist in the body almost exclusively in the form of non-dissociated boric acid. Therefore, the variety of inorganic boron compounds is commonly addressed in the toxicological literature as "boron" (B). There is a discussion concerning categorisation of inorganic boron compounds as reproductive toxins. Boron treatment of rats, mice and dogs was dose-dependently associated with testicular toxicity, characterised by inhibited spermiation at lower dose levels and by reduction of epididymal sperm counts at higher dose levels. The NOAEL for such fertility effects of boric acid in male rats (oral feeding, Sprague Dawley strain) was evaluated to be 17.5 mg B/kg bw per day. As far as developmental toxicity is concerned, oral dosing of 9.6 mg B/kg bw daily to female pregnant Sprague Dawley rats remained without effects, with foetal skeletal effects observed at higher doses. Therefore, 9.6 mg B/kg bw (oral dosing) was evaluated as NOAEL for developmental effects of boric acid. The blood level in rats, equivalent to this NOAEL, is 1270 ng B/g. As far as B-exposed humans are concerned, field studies on the effect of boron on human reproduction are possible only in a few boron-rich geographical areas. Published field studies were conducted in China's Liaoning province, the Argentinian Andes and Western Anatolia/Turkey. Particularly relevant are studies on occupationally B-exposed groups, because the potential exposure to boron is much higher in occupational compared to environmental settings. Comparison of estimated daily B exposure levels in humans and actually measured B blood levels confirms the preference of biomonitoring for exposure assessment in environmental and occupational studies. A boron blood level scaling shows that the levels of high occupational B exposures reported in China and in Turkey are compatible. Compared to the experimental B blood levels at boron-related NOAELs for male fertility and for developmental toxicity in rats, the human blood level means of the highest occupational exposure groups in China and in Turkey are lower by factors of > 4 and > 2, respectively. Basically, concentrations of B within the body that exert reproductive toxicity in humans are not reached under the conditions of human normal handling and use, including conditions of extreme occupational exposures. In consequence, all relevant results of studies into human reproductive toxicity of B are basically negative. Considering the effective doses, there is no scientific contradiction between experimental and human results of B reproductive toxicity.

Evaluation of the DNA damage in lymphocytes, sperm and buccal cells of workers under environmental and occupational boron exposure conditions.

Industrial production and use of boron compounds have increased during the last decades, especially for the manufacture of borosilicate glass, fiberglass, metal alloys and flame retardants. This study was conducted in two districts of Balikesir; Bandirma and Bigadic, which geographically belong to the Marmara Region of Turkey. Bandirma is the production and exportation zone for the produced boric acid and some borates and Bigadic has the largest B deposits in Turkey. 102 male workers who were occupationally exposed to boron from Bandirma and 110 workers who were occupationally and environmentally exposed to boron from Bigadic participated to our study. In this study the DNA damage in the sperm, blood and buccal cells of 212 males was evaluated by comet and micronucleus assays. No significant increase in the DNA damage in blood, sperm and buccal cells was observed in the residents exposed to boron both occupationally and environmentally (p = 0.861) for Comet test in the sperm samples, p = 0.116 for Comet test in the lymphocyte samples, p = 0.042 for micronucleus (MN) test, p = 0.955 for binucleated cells (BN), p = 1.486 for condensed chromatin (CC), p = 0.455 for karyorrhectic cells (KHC), p = 0.541 for karyolitic cells (KLY), p = 1.057 for pyknotic cells (PHC), p = 0.331 for nuclear bud (NBUD)). No correlations were seen between blood boron levels and tail intensity values of the sperm samples, lymphocyte samples, frequencies of MN, BN, KHC, KYL, PHC and NBUD. The results of this study came to the same conclusions of the previous studies that boron does not induce DNA damage even under extreme exposure conditions.