Brenda Carver

Perinatal toxicity of maneb, ethylene thiourea, and ethylenebisisothiocyanate sulfide in rodents

The potential of the fungicide maneb and two of its metabolites, ethylenebisisothiocyanate sulfide (EBIS) and ethylene thiourea (ETU), to induce perinatal toxicity in four species of rodents was investigated. The compounds were admininistered to rats and mice during the period of organogenesis, and ETU was also administered to rats and mice during the period of organogenesis, and ETU was also administered by oral gavage for a similar period to hamsters and guinea pigs. Treatment also continued through the lactational period in groups of rats that were allowed to give birth. Fetuses were examined for signs of toxicity, including terata, and neonates for reflex developement and open-field behavior. Maneb produced hydrocephalus in fetuses in litters of rats receiving 480 mg/kg . d. No fetotoxic effects were noted in litters of rats receiving EBIS at doses at high as 30 mg/kg . d. ETU proved to be a potent teratogen in the rat. Among the effects seen at doses of 40 mg/kg . d or greater were hydrocephalus, encephalocele, kyphosis, and various defects of the digits. Neither maneb (up to 1500 mg/kg . d), ETU (up to 200 mg/kg . d), nor EBIS (up to 200 mg/kg . d) elicited signs of fetal toxicity in the mouse. ETU also failed to result in fetal toxicity when administered to the hamster (100 mg/kg . d) or the guinea pig (100 mg/kg . d). Neither maneb nor EBIS produced significant dose-related alterations in the behavioral development of perinatally exposed rat neonates. At doses that also produced neonatal hydrocephalus, ETU produced significant increases in the open-field activity of the neonates. In addition to the perinatal effects noted above, both maneb and EBIS caused maternal limb paralysis in the rat, an effect not noted in the mouse at much higher doses.

Fetotoxicity and cataractogenicity of mirex in rats and mice with notes on Kepone

Abstract The fetotoxic potential of mirex in the rat and the cataractogenic potential of mirex and Kepone in the rat and mouse have been studied. Signs of fetal toxicity including edema, undescended testes, and reduced weight were seen in litters of CD rats treated with 7 mg/kg/day of mirex on Days 7–16 of gestation. The postpartum administration of mirex to both rat and mouse dams resulted in dose-related incidences of irreversible cataracts. Outlined lenses were also noted in pups in treated litters. A total dose of 10 mg/kg mirex administered either singly or over 4 days during the first week after birth was cataractogenic in both albino (CD, Sherman strains) and nonalbino (Long-Evans) rats. A total dose of 12 mg/kg was cataractogenic in the CD-1 mouse. Cataracts were present by Day 13 (eye-opening) in the rat pups and generally appeared after Day 20 in the mouse. The maternal administration of mirex also resulted in dose-related decreases in weight and viability in their litters. The postpartum administration of Kepone to maternal rats and mice did not result in any alterations in the lenses of the pups.

Toxicity of mercuric chloride to the developing rat kidney. I. Postnatal ontogeny of renal sensitivity.

Although the sensitivity of the adult rat kidney to mercuric chloride has been widely reported, the degree to which this toxicant affects the developing kidney is unknown. Therefore, this study examined the effects of HgCl2 on renal function during postnatal maturation. Sprague-Dawley rats were treated with a single sc injection of 5 mg/kg HgCl2 on Day 1, 8, 15, 22, or 29 after birth. The effects on renal function, histology, and morphology were assessed 24, 48, and 120 hr after each treatment. Measurements of renal function included urine volume, osmolality, the ability to concentrate urine during water deprivation, urinary pH, chloride and protein content, tests for glucosuria, hematuria, and various serum chemistry parameters. Rats were killed and their kidneys processed and examined by light microscopy. The renal sensitivity to HgCl2 increased throughout maturation for every parameter measured. No pups treated with HgCl2 on Day 1 died, but mortality increased to almost 20% in rats treated 22 and 29 days after birth. Body weight was unaffected in Day 1 animals, but was decreased at 120 hr post-treatment in three of the other four age groups. Kidney weights were unaffected in 1- and 8-day olds, but were increased by 10 to 55% in rats that were 15, 22, and 29 days old. Urine volume was increased 48 to 72 hr following treatment at all ages. The ability to concentrate urine in response to water deprivation was compromised in all animals with the exception of those treated on Day 1, and was decreased to the greatest extent in 29-day-olds. Urinary chloride concentration was decreased in Day-22 animals at 24 and 48 hr, and in Day-29 rats at all times observed after injection. Urinary pH was more acidic in treated suckling pups, and more basic in treated pups after weaning on Day 22. Urinary protein content was increased after exposure in all but the pups treated on Day 1. Serum creatinine was increased at 120 hr after injection in Day-8 rats, and 24 and 48 hr after injection in older rats. Glucosuria and hematuria occurred with increasing frequency as the pups matured. Histological evaluation revealed some cortical tubular dilatation in rats treated on Day 1 or Day 8; there was tubular necrosis in older rats. For all parameters observed, the neonatal kidney was largely insensitive to HgCl2 toxicity; however, a trend toward increased sensitivity with increasing age was demonstrated.

Toxicity of mercuric chloride to the developing rat kidney. II. Effect of increased dosages on renal function in suckling pups

It has been demonstrated that the sensitivity to HgCl2 nephrotoxicity increases with maturity in the rat, and that neonates are largely unaffected by a dose of 5 mg/kg. In the present study, immature rat pups were exposed to higher doses of HgCl2 to determine whether this effect was attributable to a quantitative or qualitative difference in the renal sensitivity to HgCl2. Sprague-Dawley rats were injected with a single dose of 5, 7.5, 10, 12.5, 20, or 30 mg/kg on Postnatal Day 1; 5, 7.5, 10, 12.5, 15, or 20 mg/kg on Day 8; or 6.25, 7.5, 10, or 12.5 mg/kg on Day 15. Renal function was evaluated at 24, 48, and 120 hr after treatment by measuring urine volume, osmolality, urinary pH, and chloride content, the ability to concentrate urine during water deprivation, and the presence of protein, glucose, or hemoglobin in urine. Animals were then killed and their kidneys weighed. A dose of 20 mg/kg was needed to induce mortality in pups treated at 1 day of age, and 15 mg/kg was needed in pups treated at 8 days of age. In contrast, the 6.25-mg/kg dose given to 15-day-old pups produced some mortality, and all rats given higher doses at 15 days of age died within 2 days. There was marked oliguria or anuria in the rats that died. Kidney weight was increased in a dose-related fashion at all ages. In those animals not rendered oliguric by the treatment, urine volume increased and the ability to secrete a more concentrated urine during water deprivation decreased. Urinary pH was decreased in a dose-related manner. Urinary chloride excretion was temporarily decreased after HgCl2 treatment on Day 1 , but was increased thereafter. Proteinuria, glucosuria, and hematuria were detected in the treated rats, again increasing in frequency and severity with age and dose.

Toxicity of sodium fluoride to the postnatally developing rat kidney

The adult rat kidney is an important target organ for sodium fluoride; however, the toxicity of fluoride to the developing kidney is unknown. This study examined renal function following NaF exposure during the first 4 weeks after birth. Sprague-Dawley rats received a single ip injection of 0, 30, or 48 mg/kg NaF on postnatal Day 1, 8, 15, or 29. Alterations in renal function, histology, and morphology were determined 24, 48, and 120 hr after exposure. Measurements of renal function included urine volume, osmolality, the ability to concentrate urine during water deprivation, urinary pH, and chloride content. Rats were then sacrificed and their kidneys processed for observation by light microscopy. Some minor alterations in renal function were observed in the three youngest age groups after NaF exposure. These changes included decreased body weight after treatment with 30 or 48 mg/kg NaF but increased kidney-body weight ratio in the 48 mg/kg group on Day 1; decreased urinary pH in both dose groups after treatment on Day 1 or 8; increased urinary volume 120 hr after treatment on Day 8; and decreased chloride excretion in the 48 mg/kg group 24 hr after injection on Day 1. None of these effects was severe. In contrast to these results, marked renal toxicity was observed in postweaning rats treated on Day 29. The NaF exposure resulted in increased kidney weight and kidney/body weight ratio, profound diuresis, decreased urinary osmolality, and decreased ability to concentrate urine during water deprivation. Urinary chloride excretion was decreased for the first 2 days after NaF exposure, then increased in water-deprived rats 120 hr after treatment. Glucosuria and hematuria were present for 2 days after treatment with 48 mg/kg. Histological lesions were apparent in the proximal tubules of the treated Day 29 rats. Thus, the kidney of the suckling rat is largely unresponsive to NaF toxicity. Renal sensitivity increases abruptly after weaning in the Day 29 rat.