Evaluation of 60 chemicals in a preliminary developmental toxicity test.

The number of chemicals in commerce which have not been evaluated for potential developmental toxicity is large. Because of the time and expense required by conventional developmental toxicity tests, an abbreviated assay is needed that will preliminarily evaluate otherwise untested chemicals to help prioritize them for conventional testing. A proposed short-term in vivo assay has been used in a series of studies in which a total of 60 chemicals were tested. Some were independently tested two or four times each. In this preliminary test, pregnant mice were dosed during mid-pregnancy and were then allowed to deliver litters. Litter size, birth weight, and neonatal growth and survival to postnatal day 3 were recorded as indices of potential developmental toxicity. Results in this assay and conventional mouse teratology tests were generally concordant. Conventional data were available for 14 chemicals (ten teratogens, one fetotoxin, three nonteratogens), of which 11 (nine teratogens, one fetotoxin, one nonteratogen) produced evidence of developmental toxicity. This included conventional data for three chemicals (ethylene glycol, diethylene glycol dimethyl ether, and triethylene glycol dimethyl ether) that were untested before the present study. As high priority candidates for conventional testing on the basis of results here, all were subsequently studied in a standard teratology assay and were confirmed to be teratogenic in mice. Additionally, one of them (ethylene glycol) plus a fourth high priority candidate for conventional study (diethylene glycol monomethyl ether) were subsequently tested in rats and were found to be teratogenic in that species.

Hydrocarbon nephropathy in male rats: identification of the nephrotoxic components of unleaded gasoline.

Previous subchronic and/or chronic inhalation studies of unleaded gasoline and a variety of petroleum naphthas, solvents, and distillates have shown that these complex materials are capable of inducing a distinctive nephropathy which appears limited to male rats. Therefore a series of gavage screening studies using male F-344 rats was conducted on components of gasoline to more clearly identify the major contributors to this nephrotoxicity. The dosing regimen consisted of 20 doses administered once daily, 5 days per wk for 4 wk. Tested were 15 pure hydrocarbon compounds typically found in unleaded gasoline boiling range, 4 naphtha streams representative of those commonly used to blend gasolines and 3 distillation fractions covering the less volatile portions of gasoline. The results revealed that the alkane (paraffin) components were primarily responsible for the nephrotoxic activity seen in unleaded gasoline, with a positive structure-activity response relating the degree of alkane branching to the potency of the nephrotoxic response. In addition, the nephrotoxic activity observed with the naphtha streams and distillation fraction correlated well with the proportion of branched alkanes contained in each.

Reproductive capacities of control bobwhite quail (Colinus virginianus) during one-generation reproduction studies.

The Bobwhite quail (Colinus virginianus) is the avian model of choice for testing the reproductive impairment potential of pesticides and environmental contaminants. While the literature contains numerous reports on the effects of pesticides on eggshell development for quail, mallards and other avian species (Haegele and Tucker, 1974; Kolaja, 1977; Jenkins et al., 1974) limited control data for reproductive evaluation of pesticides can be found. This paper summarizes the control data from three one-generation reproductive studies in Bobwhite quail. One male and two female adult quail were housed in clean pens with tap water and game bird breeder ration available ad libitum. The pre-laying cycle was ten weeks in duration. The photoperiod was seven hours of light per day for the first eight weeks and was increased to 17 hours of light per day in order to induce egg laying. Eggs were collected daily for eight weeks and incubated. Biweekly, one egg from each pen was removed and used for determination of eggshell thickness. The mean reproductive indices for these studies are: Eggs cracked/Eggs laid--8.2%, Viable 11-day embryos/Eggs set--73.6%, Viable 21-day embryos/Viable 14-day embryos--98.9%, Hatchlings/Viable 21-day embryos--82.0%, 14-day survivors/Hatchlings--76.3%. The mean eggshell thickness for 144 eggs was 0.301 mm.

Results of testing fifteen glycol ethers in a short-term in vivo reproductive toxicity assay.

Fifteen glycol ethers were investigated for their potential to cause adverse reproductive toxic effects using an in vivo mouse screening bioassay. Pregnant mice were orally dosed once per day on days 7 through 14 of gestation at concentrations causing 0 to 41% maternal mortality. Reproductive endpoints included pup survival in utero (percent of live litters/pregnant survivors), pup perinatal and postnatal survival (number of live pups per litter, number of dead pups per litter, and pup survival to 2.5 days of age), and pup body weight statistics (weight at birth and weight at 2.5 days of age). The study was conducted in two phases: a dose range-finding phase using nonpregnant female mice, and a definitive reproductive phase using time-mated mice. The range-finding phase sought to identify, for each chemical, the maternal LD10 as the target dose. However, based upon reproductive phase results, such an exact dose was impractical to achieve. Thus, a range from the LD5 to the LD20 was considered a sufficient challenge dose that would not affect results due to high mortality, i.e., greater than the LD20. Glycol ethers were assigned to groups having different priorities for further testing based upon whether a sufficient challenge dose was administered and the degree of effects recorded for each chemical.(ABSTRACT TRUNCATED AT 250 WORDS)

Six-month feeding study of fenvalerate in dogs.

Groups of six male and six female Beagle dogs were fed diets containing 0, 250, 500, or 1000 ppm fenvalerate for a period of 6 months. Prominent in-life observations related to treatment were emesis, head shaking, biting of the extremities, ataxia, and tremors. One high-dose male dog was sacrificed in extremis during the study period. Mean body weights of 1000-ppm female dogs were significantly lower than those of controls. Red blood cell counts and hematocrit and hemoglobin values in high-dose male and female dogs were significantly lower than those of controls at most sampling intervals. Serum cholesterol and alkaline phosphatase levels were also increased primarily in the high-dose group. Ophthalmic examination revealed changes in retinal vessel tortuosity in some mid- and high-dose dogs. Hepatic multifocal microgranulomata were observed in control and treated dogs microscopically. These changes increased in incidence and severity with dose and were considered to be related to treatment. Histiocytic cell infiltrate in mesenteric lymph nodes in some 500- and 1000-ppm female and 1000-ppm male dogs was the only other treatment-related microscopic effect.

Reproductive capacities of control mallard ducks (Anas platyrhynchos) during a one-generation reproduction study.

The Mallard duck (Anas Platyrhynchos) is the waterfowl model of choice for testing the reproductive impairment of pesticides and environmental contaminants. The literature contains numerous reports on the effects of pesticides on egg shell development for mallards, quail and other avian species. Limited control data for reproductive evaluation of pesticides can be found. This paper summarizes one generation reproduction results from 75 control female mallard ducks. One male and five female adult ducks were housed in clean pens with tap water and game bird breeder ration available ad libitum. The pre-egg laying cycle was ten weeks in duration. For the first eight weeks, the photoperiod was seven hours light per day, after which the photoperiod was increased to 17 hours to induce egg laying. Eggs were collected daly for eight weeks and incubated. Shell thickness was measured on one egg from each pen bi-weekly. The mean reproductive indices are as follows: Eggs Cracked/Eggs Laid - 2.18%; Viable 11-Day Embryos/Eggs Set-85.2%; Live 21-Day Embryos/Viable 11-Day Survivors-97.6%; Hatchlings/Live 21-Day Embryos-80.6%; and 14-Day Survivors/Hatchlings-89.3%. The mean egg shell thickness for 60 eggs is 0.378 millimeters.

Inhibition of hepatic uptake of alpha aminoisobutyric acid by ethanol: effects of pyrazole and metabolites of ethanol.

Ethanol inhibits the uptake of AIB by the isolated perfused rat liver. However, if the metabolism of ethanol is blocked by pyrazole, there is no reduction in accumulation of AIB by the liver. Acetaldehyde and acetate, metabolites of ethanol have no effect on AIB uptake by the liver. The inhibition of urea synthesis by ethanol is also prevented by pyrazole. Neither of the metabolites of ethanol inhibit urea synthesis in the isolated liver.