Oral (Drinking Water) Two-Generation Reproductive Toxicity Study of Bromodichloromethane (BDCM) in Rats

Abstract

Bromodichloromethane (BDCM) was tested for reproductive toxicity in a two-generation study in CRL SD rats. Thirty rats/sex/ group/generation were continuously provided BDCM in drinking water at 0 (control carrier, reverse osmosis membrane-processed water), 50,150, and 450 ppm (0, 4.1 to 12.6, 11.6 to 40.2, and 29.5 to 109.0 mg/kg/day, respectively). Adult human intake approximates 0.8 microg/kg/day (0.0008 mg/kg/day). P and F1 rats were observed for general toxicity (viability, clinical signs, water and feed consumption, body weights, organ weights [also three weanling Fl and F2 pups/sex/litter], histopathology [10/sex, 0- and 450-ppm exposure groups]) and reproduction (mating, fertility, abortions, premature deliveries, durations of gestation, litter sizes, sex ratios, viabilities, maternal behaviors, reproductive organ weights [also three weanling Fl and F2 pups/sex/ litter], sperm parameters, and implantations. F1 rats were evaluated for age at vaginal patency or preputial separation. Ten P and F1 rats/sex from the 0- and 450-ppm exposure groups and rats at 50 and 150 ppm with reduced fertility were evaluated for histopathology (gross lesions, testes, intact epididymis, all F1 dams for number of primordial follicles). Developmental parameters in offspring included implantation and pup numbers, sexes, viabilities, body weights, gross external alterations, and reproductive parameters (Fl adults). Toxicologically important, statistically significant effects at 150 and/or 450 ppm included mortality and clinical signs associated with reduced absolute and relative water consumption, reduced body weights and weight gains, and reduced absolute and relative feed consumption (P and F1 rats). Significantly reduced body weights at 150 and 450 ppm were associated with reduced organ weights and increased organ weight ratios (% body and/or brain weight). Histopathology did not identify abnormalities. Small delays in sexual maturation (preputial separation, vaginal patency) and more Fl rats with prolonged diestrus were also attributable to severely reduced pup body weights. Mating, fertility, sperm parameters, and primordial ovarian follicular counts were unaffected. The no-observable-adverse-effect level (NOAEL) and the reproductive and developmental NOAELs for BDCM were at least 50 ppm (4.1 to 12.6 mg/kg/day), 5125 to 15,750 times the human adult exposure level, if delayed sexual maturational associated with severely reduced body weights is considered reproductive toxicity. If considered general toxicity, reproductive and developmental NOAELs for BDCM are greater than 450 ppm (29.5 to 109.0 mg/kg/day), or 36,875 to 136,250 times the human adult exposure level. Regardless, these data indicate that BDCM should not be identified as a risk to human reproductive performance or development of human conceptuses.

Chlorination by-products in tap water and semen quality in England and Wales

“…Evidence for BDCM in drinking water affecting semen quality in laboratory animals is mixed. In one study, rats fed 39 mg/kg/day of BDCM in drinking water over 52 weeks exhibited poor sperm motility parameters and no signs of systemic toxicity,13 while in a second investigation, up to 109 mg/kg/day of BDCM produced no effect 12. These heterogenous results could be due to either the sensitivity of the motility endpoints investigated or differential sensitivity of the rats (F344 and Sprague–Dawley) 32.…”

“…DBAA appears to be a stronger testicular toxicant than the dichloro- analogue4 and mixtures of DBAA and BCAA suggest that the haloacid-induced decreases in SP22 proteins are additive, possibly synergistic 9. Few studies have investigated trihalomethanes (THMs), a class of volatile DBPs that are the most widely occurring by-products in public water supplies in the UK, and no evidence was found for any reproductive effects for bromoform,11 and inconclusive evidence for bromodichloromethane (BDCM) 12 13…”

Identification of developmentally toxic drinking water disinfection byproducts and evaluation of data relevant to mode of action

“…Human, DW, epi (Waller et al, 1998) Human, DW, epi, time to pregnancy as indicator of possible early pregnancy loss (MacLehose et al, 2008) In the rat, BDCM decreases serum LH, resulting in decreased serum progesterone; F344 has less constitutive LH than SD, LH in rats is analogous to hCG in humans; hCG or progesterone prevented full-litter resorption in rats treated with BDCM (Narotsky and Laffan, 2004;Bielmeier et al, 2001Bielmeier et al, , 2002Bielmeier et al, , 2004Bielmeier et al, , 2007 Human, DW, epi (Savitz et al, 2005(Savitz et al, , 2006 SD rat G-aqueous emulphor (Bielmeier et al, 2001(Bielmeier et al, , 2002 BDCM inhibited hCG-stimulated progesterone secretion by rat corpora lutea in vitro (Bielmeier et al, 2007) F344 rat, G-aqueous emulphor (Bielmeier et al, 2001(Bielmeier et al, , 2004 SD rat, DW (Christian et al, 2001a) BDCM inhibited differentiation of cultured human placental trophoblast cells and decreased hCG secretion and intracellular hCG (Chen et al, 2003(Chen et al, , 2004 F344 rat, G-aqueous emulphor-slight but not significant increase (Narotsky et al, 1997a) SD rat, rabbit, DW, fertility not affected (Christian et al, 2002a) Rabbit, DW, limited data suggest BDCM reaches placenta and fetus (Christian et al, 2001b) F344 rat, G-corn oil (Narotsky et al, 1997a) SD rat, DW (NTP, National Toxicology Program, 1998a) Generally, toxicity may be mediated through metabolism to reactive and toxic intermediates (ILSI, 1999) F344 rat, G-corn oil (Narotsky et al, 1992) Dibromochloromethane -Human, DW, epi (Waller et al, 1998) Generally, toxicity may be mediated through metabolism to reactive and toxic intermediates (ATSDR, 2003;ILSI, 1999) Human, DW, epi (Savitz et al, 2005(Savitz et al, , 2006 SD rat, DW (NTP, National Toxicology Program, 1996) Bromoform F344 rat, G-corn oil, developmental toxicity screen…”

Study of tolerance of enterobacteria to chlorine-based biocides in experimental models using chromogenic indicator tests

“…Treatment with chlorine-bearing biocides protects the products from cross-seeding of the food infection agents and toxic infection, and extends shelf life of the products. However the use of chlorine is associated with a number of adverse effects including the formation of trihalomethanes that demonstrate toxic and carcinogenic activity: chloroform dihlorbrommetana, dibromochloromethane and bromoform [4,5,6,8]. Overall, observance of the maximum permissible levels helps avoid direct health risks such as toxic, allergic and other reactions caused by food products and drinks with residues of those substances.…”