John L. Egle

Retention of Inhaled Formaldehyde, Propionaldehyde, and Acrolein in the Dog

Aldehydes in the vapor phase of cigarette smoke are of considerable interest in terms of tissue irritation, ciliatoxicity, and other effects. This study deals with the handling by the canine respiratory tract of formaldehyde, acrolein, and propionaldehyde, which are present in the gas phase in relatively high concentrations. Specific aims included measurement of retention of each compound by the entire respiratory tract and by upper and lower portions under varying conditions of ventilatory rate, tidal volume, and concentration inhaled. Uptake of formaldehyde was always close to 100% regardless of any other factor. The total-tract retention of propionaldehyde and acrolein was much lower and of similar magnitude. In terms of regional uptake, retention of propionaldehyde was greater than that of acrolein in the lower tract and less than that of acrolein in the upper tract.

Toxicological evaluation of μ-agonists part I: Assessment of toxicity following 30 days of repeated oral dosing of male and female rats with levo-alpha-acetylmethadol HCl (LAAM)†

This study evaluated levo‐alpha‐acetylmethadol hydrochloride (LAAM), a long‐acting morphine‐like (μ) agonist approved in 1993 to treat opiate dependence. Sprague‐Dawley rate (20/sex/group) were gavaged with doses of 3.0–33.5 mg kg−1 for 30 days followed by a 14‐day drug‐free recovery period. Treatment‐related effects included dose‐dependent CNS depression, decreased food consumption and body weight gain, reddish urine and abdominal staining. Tolerance developed by day 7. Mortality was dose‐dependent; deaths occurred predominantly during the first week. Increased alanine aminotransferase (SGOT, AST) and lactate dehydrogenase (LDH), observed only in high‐dose males, were associated with findings in liver. Decreases in spleen/brain weight and increases in brain/body weight ratios were seen in both sexes. Decreases in weights of heart, liver and kidney achieved statistical significance only for high‐dose groups. Kidneys of mid‐ and high‐dose groups displayed intertubular mineral/crystal deposition, focal corticomedullary mineralization and focal regenerative tubular epithelium. Centrilobular hypertrophy was observed in livers of high‐dose males and mid‐ and high‐dose females. Following the recovery period, decreased body weights and increased brain/body weight ratios occurred in mid‐dose males and low‐dose females. Weights of liver and kidney and organ/brain weight ratios were decreased in mid‐dose males. Histopathological findings observed in kidneys and livers had abated.

Short-Term Toxicity (One-and Ten-Day Gavage) of Barium Chloride in Male and Female Rats

To assess adverse effects that might be caused by an event resulting in high levels of barium in drinking water, rats were gavaged with barium chloride (BaCl2 at dosage levels of 30, 100, and 300 mg/kg in a 1-day study and at 100, 145, 209, and 300 mg/kg for 10 days, and the effects were determined. LD50 values for male and female rats were found to be 419 (352–499) and 408 (342–487) mg/kg BaCl2, respectively. In the 1-day exposure study, decreases in body weight and liver/brain weight ratios and increase in kidney weight as a percentage of body weight appeared to be related to barium ingestion at 300 mg/kg. After 10 days of exposure to barium, survival of females was substantially lower at 300 mg/kg. A reduction in ovaries/brain ratio at 300 mg/kg appeared to be barium-induced. There was a decrease in BUN at 300 mg/kg in males and at all dose levels in females. No other effects were attributed to barium. Histopathological findings were negative in both the 1-and 10-day studies. It is concluded that short-term oral exposure to BaCl2 at doses up to 209 mg/kg produces no significant adverse health effects.

Respiratory retention and acute toxicity of furan.

The respiratory tract retention of furan has been studied in dogs as part of a broad investigation of compounds found in the vapor phase of cigarette smoke. The LD50 of furan has also been determined in mice and rats and the LC50 in mice. Respiratory uptake of furan was between 90 and 95%, varying inversely with the ventilatory rate. Retention was not affected by tidal volume changes but was directly related to concentration inhaled. Intraperitoneal LD50 values were 5.2 mg/kg for rats and 7.0 mg/kg for mice. The LC50 for mice was 0.12 microgram/mL. These results indicate the high toxicity of furan and that it is readily absorbed by the inhalation route.

Evaluation of the Safety of Tara Gum as a Food Ingredient: A Review of the Literature

Tara gum is a potential replacement for locust bean gum for use as a formulation aid, stabilizer, and thickener for food applications. In addition to biochemical and digestibility data, studies assessing the toxicity of tara gum are reviewed. The latter includes three 90-day feeding studies, two in rats and one in dogs; two 2-year feeding studies in rats and one in mice; a 3-generation reproduction study with rats and a reproductive toxicity and teratogenicity study with rats; an Ames reverse mutation assay with five Salmonella typhimurium strains; and a micronucleus test in mice. The feeding studies did not indicate any significant adverse effects attributable to tara gum at the maximum dietary level of 5%. The results of the genotoxicity studies were negative. It is concluded that tara gum meets the scientific standards required for classification as a GRAS food ingredient.

Reproductive Toxicity and Lack of Dominant Lethal Effects of 2,4-Dinitrotoluene in the Male Rat

Adult male Sprague Dawley rats were gavaged with 2,4-dinitrotoluene (2,4-DNT) dissolved in corn oil at 0, 60, 180, or 240 mg/kg/day for five days. A single oral dose (0.5 mg/kg) of triethylenemelamine was used as a positive control. Induction of dominant lethal events was scored on the basis of early fetal deaths. At the two lower doses, no consistent changes were observed in the numbers of pre-implantation losses, implantation sites, or living or non-living fetuses. The highest dose of 2,4-DNT tested resulted in a marked decrease in the numbers of sperm-positive females (determined by microscopic examination of vaginal smears for sperm) and pregnant females. These two effects diminished in the latter weeks of mating. The low number of pregnant females at the highest dose made meaningful statistical evaluations difficult. The results indicate that 2,4-DNT does not cause dominant lethal mutations but does adversely affect reproductive performance.

Respiratory retention of inhaled toluene and benzene in the dog.

This study deals with the inhalation of toluene and benzene found in the vapor phase of cigarette smoke. Determined in this study were the uptake of each substance by the total respiratory tract and by the upper and lower portions under varying conditions of ventilatory rate, tidal volume, and concentration inhaled. Retention by the total tract of toluene fell within the range of 91-94% at all ventilatory rates seen, indicating no relationship between rate and retention. With benzene, total tract retention varied from 88 to 68% with an inverse relationship between retention and rate apparent. This relationship was seen in all types of experiments conducted with benzene. Upper tract retention revealed an uptake of about 89% for both one- and two-way experiments with toluene. In the benzene experiments retention varied from 80 to 61% and from 81 to 63% in the one- and two-way procedures, respectively. Mean lower tract retention was 90% with toluene at all ventilatory rates considered. Benzene retention varied from 74 to 61% as the rate increased from 6 to 18 inhalations/min.

Retention of Inhaled Aeetaldahyde in the Dog

This study deals with respiratory tract retention of inhaled acetaldehyde vapor by dogs. Experiments were designed to measure uptake by the entire respiratory tract and by upper and lower portions and the influence of tidal volume and! of concentration Inhaled, A prime objective was to determine whether respiratory uptake of acetaldehyde in an animal system is comparable to previously reported human respiratory uptake. If so, this would make more meaningful additional types of experiments with acetaldehyde and other compounds in dogs alone. Total respiratory tract retention of acetaldehyde in dogs was found to be very close to human retention values and inversely related to ventilatory rate In the same manner. Uptake was also found to be higher in the upper tract than the lower tract and no related to changes in concentration inhaled or tidal volume.

The Acute and Subchronic Toxicity in Rats of Trans-1,2-Dichloroethylene in Drinking Water

Trans-1,2-dichloroethylene was administered either by gavage (acute studies) or in drinking water (subchronic studies) to male and female Sprague-Dawley derived Charles River rats. The acute oral LD50 was 7902 mg/kg for males and 9939 mg/kg for females. Decreased activity, ataxia, and depressed respiration preceded death. In the subchronic study, rats received theoretical daily doses of 500, 1500, and 3000 mg trans-1,2-dichloroethylene/kg body weight/day for 90 consecutive days. The actual daily doses were 402, 1314, and 3114 mg/kg for males and 353, 1257, and 2809 mg/kg for females. There were no compound-related deaths. There were no consistently significant compound-related dose-dependent adverse effects on any of the hematological, serological, or urinary parameters evaluated. There were dose-dependent increases in kidney weights and ratios in treated females. There were no compound-related gross or histological effects. No specific organ site toxicity could be identified in these studies. These data suggest that the toxicity from exposure to trans-1,2-dichloroethylene in drinking water apparently is low and probably does not constitute a serious health hazard.

Single-Breath Retention of Acetaldehyde in Man

The single-breath retention of acetaldehyde vapor by the respiratory tract of human subjects was measured in this study. Experiments were performed in which the volume inhaled and duration of inhalation and exhalation were varied. Some experiments involved breath holding of various time intervals. A direct relationship was found to exist between the volume inhaled and the percent taken up. There was an inverse relationship between rate of inhalation and retention. At all inspiratory rates and tidal volumes, there was an increase in retention as breath-holding time became longer. The humidity of the inhaled vapor had no effect on acetaldehyde retention. Although several factors were found to affect uptake, it appears that the volume inhaled is the most important in determining single-breath retention.