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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 "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,β-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)., (© 2022. The Author(s).)

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 Bandırma 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Because of the high pK a 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.

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 Balıkesir; Bandırma and Bigadic, which geographically belong to the Marmara Region of Turkey. Bandırma 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 Bandırma 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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Boron (B) compounds are essential for plants and animals and beneficial for humans in nutritional amounts. I animals and humans increasing evidence have shown beneficial effects on B compounds on nutrition and on antioxidant status. The genotoxic effects of environmental B exposure in women living in boron-rich and boron-poor areas was examined in this study. For this purpose, the DNA damage in the lymphocytes and buccal cells of females were assessed by Comet and micronucleus (MN) assays respectively. No significant difference was observed in the DNA damage of the lymphocytes of B exposed groups of female volunteers in Comet assay. Even buccal micronucleus (MN) frequency observed in the high exposure group was significantly lower than the low exposure group (p < 0.05). 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., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Boron-associated shifts in sex ratios at birth were suggested earlier and attributed to a decrease in Y- vs. X-bearing sperm cells. As the matter is pivotal in the discussion of reproductive toxicity of boron/borates, re-investigation in a highly borate-exposed population was required. In the present study, 304 male workers in Bandirma and Bigadic (Turkey) with different degrees of occupational and environmental exposure to boron were investigated. Boron was quantified in blood, urine and semen, and the persons were allocated to exposure groups along B blood levels. In the highest ("extreme") exposure group (n = 69), calculated mean daily boron exposures, semen boron and blood boron concentrations were 44.91 ± 18.32 mg B/day, 1643.23 ± 965.44 ng B/g semen and 553.83 ± 149.52 ng B/g blood, respectively. Overall, an association between boron exposure and Y:X sperm ratios in semen was not statistically significant (p > 0.05). Also, the mean Y:X sperm ratios in semen samples of workers allocated to the different exposure groups were statistically not different in pairwise comparisons (p > 0.05). Additionally, a boron-associated shift in sex ratio at birth towards female offspring was not visible. In essence, the present results do not support an association between boron exposure and decreased Y:X sperm ratio in males, even under extreme boron exposure conditions.

Boric acid and sodium borates are currently classified in the EU-CLP regulation as "toxic to reproduction" under "Category 1B", with hazard statement of H360FD. However, so far field studies on male reproduction in China and in Turkey could not confirm such boron-associated toxic effects. As validation by another independent study is still required, the present study has investigated possible boron-associated effects on male reproduction in workers (n = 212) under different boron exposure conditions. The mean daily boron exposure (DBE) and blood boron concentration of workers in the extreme exposure group (n = 98) were 47.17 ± 17.47 (7.95-106.8) mg B/day and 570.6 ± 160.1 (402.6-1100) ng B/g blood, respectively. Nevertheless, boron-associated adverse effects on semen parameters, as well as on FSH, LH and total testosterone levels were not seen, even within the extreme exposure group. With this study, a total body of evidence has accumulated that allows to conclude that male reproductive effects are not relevant to humans, under any feasible and realistic conditions of exposure to inorganic boron compounds.

Boric acid and sodium borates are currently classified as being toxic to reproduction under "Category 1B" with the hazard statement of "H360 FD" in the European CLP regulation. This has prompted studies on boron-mediated reprotoxic effects in male workers in boron mining areas and boric acid production plants. By contrast, studies on boron-mediated developmental effects in females are scarce. The present study was designed to fill this gap. Hundred and ninety nine females residing in Bandirma and Bigadic participated in this study investigating pregnancy outcomes. The participants constituted a study group covering blood boron from low (< 100 ng B/g blood, n = 143) to high (> 150 ng B/g blood, n = 27) concentrations. The mean blood boron concentration and the mean estimated daily boron exposure of the high exposure group was 274.58 (151.81-975.66) ng B/g blood and 24.67 (10.47-57.86) mg B/day, respectively. In spite of the high level of daily boron exposure, boron-mediated adverse effects on induced abortion, spontaneous abortion (miscarriage), stillbirth, infant death, neonatal death, early neonatal death, preterm birth, congenital anomalies, sex ratio and birth weight of newborns were not observed.