Is Boric Acid Toxic to Reproduction in Humans? Assessment of the Animal Reproductive Toxicity Data and Epidemiological Study Results.

Boric acid and sodium borates are classified as toxic to reproduction in the CLP Regulation under "Category 1B" with the hazard statement of "H360FD". This classification is based on the reprotoxic effects of boric acid and sodium borates in animal experiments at high doses. However, boron mediated reprotoxic effects have not been proven in epidemiological studies so far. The epidemiological study performed in Bandirma boric acid production plant is the most comprehensive published study in this field with 204 voluntarily participated male workers. Sperm quality parameters (sperm morphology, concentration and motility parameters), FSH, LH and testosterone levels were determined in all participated employees as the reproductive toxicity biomarkers of males. However, boron mediated unfavorable effects on reproduction in male workers have not been determined even in the workers under very high daily boron exposure (0.21 mg B/kg-bw/day) conditions. The NOAEL for rat reproductive toxicity is equivalent to a blood boron level of 2020 ng/g. This level is higher than the mean blood boron concentration (223.89 ± 69.49 ng/g) of the high exposure group workers in Bandirma boric acid production plant (Turkey) by a factor of 9. Accordingly, classifying boric acid and sodium borates under "Category 1B" as "presumed reproductive human toxicant in the CLP regulation seems scientifically not reasonable. The results of the epidemiological studies (including the study performed in China) support for a down-classification of boric acid from the category 1B, H360FD to category 2, H361d, (suspected of damaging the unborn child).

Dinitrotoluene exposure in the copper mining industry and renal cancer: a case-cohort study.

OBJECTIVES: To evaluate the association between dinitrotoluene (DNT) exposure and renal cancer in a case-cohort study. METHODS: This case-cohort study was conducted among men born between 1920 and 1974 (n=16 441) who were gainfully employed between 1953 and 1990 in one of two copper mines in Mansfeld, Saxony-Anhalt, former German Democratic Republic, and followed up till 31 December 2006. The study included 109 cases with renal cancer identified by record linkage with the Common Cancer Registry of the New Federal States of Germany (GKR) or by a network of pathology institutes. A comparison subcohort of 999 cohort members was selected at random from the total cohort. Duration and intensity of inhalation and dermal exposure to DNT were assessed on the basis of a job exposure matrix. A time-dependent Cox proportional hazards model modified for case-cohort design was used to assess the relationship between cumulative inhalation and dermal DNT exposure and renal cancer. RESULTS: Elevated risks were found for medium (HR=2.73; 95% CI 1.00 to 7.42) and high (HR=1.81; 95% CI 0.75 to 4.33) dermal exposure to DNT. Relative risks for medium inhalation exposure to DNT were not increased (HR=0.93; 95% CI 0.48 to 1.79) while relative risks for high inhalation exposure to DNT were elevated to 1.36 (95% CI 0.84 to 2.21). We found a statistically significant HR of 2.12 (95% CI 1.03 to 4.37) for combined medium or high inhalation and medium or high dermal exposure to DNT. CONCLUSIONS: According to our case-cohort study, dermal and inhalation exposure to DNT is associated with increased renal cancer risk.

Cancer incidence among workers occupationally exposed to dinitrotoluene in the copper mining industry.

PURPOSE: Epidemiological and toxicological studies point to a potential carcinogenic effect of dinitrotoluene (DNT), particularly with respect to renal and urothelial cancer. METHODS: The cohort comprised all men born between 1920 and 1974 (n = 16,441) who were gainfully employed between 1953 and 1990 in one of two underground copper mines in Mansfeld, Saxony-Anhalt, former German Democratic Republic, and who were followed up for cancer incidence, 1961-2005. Incident cancer cases were identified by record linkage with the Common Cancer Registry of the New Laender. Standardized incidence ratios (SIR) were calculated with the general population of Saxony-Anhalt as the reference. RESULTS: Standardized incidence ratios for all cancers were not significantly elevated in the cohort (SIR = 1.04; 95 % confidence intervals (CI) 0.96-1.14). We found an increase in lung cancer (SIR = 1.29; 1.13-1.46), but not in kidney cancer (SIR = 1.01; 95 % CI 0.79-1.27) or bladder cancer (SIR = 1.04; 95 % CI 0.82-1.30). Standardized incidence ratios stratified by duration of employment with DNT exposure indicated moderately increased risks for kidney and bladder cancer in cohort members with longer exposure. CONCLUSIONS: The SIR analysis of workers in the copper mining industry in comparison with the general population of Saxony-Anhalt overall did not indicate increased risks for renal or bladder cancer. However, results by years of exposure to DNT suggested weakly increased risks for outcomes of a priori interest, bladder and kidney cancer. A subsequent case-cohort analysis including expert assessment of DNT exposure and identification of additional cancer cases from a network of pathology institutes will provide further insight into a potential etiologic role of DNT in renal and urothelial cancer.

Activities of drug metabolizing enzymes in bovine colon epithelial cell cultures.

The metabolic competence of cultured bovine colon epithelial cells was evaluated by determining activities of phase I and II enzymes in colonocytes cultured for different intervals (maximum of 10 days) compared with activities measured in freshly isolated cells. Cytochrome p50 1A1-associated 7-ethoxyresorufin O-deethylase (EROD) activity was detectable in freshly isolated colonocytes and in colon cells maintained in culture for up to 5 days. In contrast to liver samples, cytochrome p50 3A4-associated 7-benzyloxyresorufin O-debenzylase (BROD) activity was not detectable in bovine colon cells. Prostaglandin H synthase-mediated production of prostaglandin E(2) was found in freshly isolated and also in cultured colonocytes. Both isoenzymes (COX 1 and COX 2) were detected in cultured cells. To examine phase II metabolic potency, activities of N-acetyltransferases 1 and 2, of phenol and amino sulfotransferases, of glutathione S-transferases alpha, mu, pi and theta and of UDP-glucuronyltransferase were measured. N-Acetyltransferase (NAT) activity (substrate p-aminobenzoic acid, PABA, a diagnostic substrate for the human NAT-1 enzyme) was stable under culture conditions and during the observed culture period comparable to that of freshly isolated cells. In contrast, sulfamethazine, a specific substrate for NAT-2, was not acetylated, neither in bovine colon cells nor in bovine liver samples. Whereas activity of amino sulfotransferase (substrate 2-naphthylamine) decreased continuously during the entire culture period, the activity of phenol sulfotransferase (substrate 1-naphthol) decreased only slowly. Activity of total glutathione S-transferases (alpha, mu, and pi) (substrate 1-chloro-2,4-dinitrobenzene) decreased after 2 days in culture, but was stable during the following culture period. Activity of glutathione S-transferase theta (substrate epoxy-3-nitrophenoxypropane) changed during the culture period. At the beginning and the end (after 10 days) of the culture period maximum activity was measured. Activity of UDP-glucuronyltransferase increased during the culture period reaching a maximum after 7 days. The results show that cultured bovine epithelial colon cells express several enzyme activities required for the biotransformation of xenobiotics.