Scientific principles for evaluating the potential for adverse effects from chlorinated organic chemicals in the environment.

The term chlorinated chemicals is used to describe diverse groups of chemicals of varying chemical structure, including those used in water disinfection, as well as numerous aliphatic, aromatic, and polycyclic chlorinated substances. This report elaborates a number of scientific principles that govern the evaluation of the potential for chlorinated organic chemicals to cause adverse effects on the environment and to human health. The purpose of the report is to demonstrate the importance of applying these scientific principles in the evaluation of potential adverse effects of chlorinated organic chemicals. The four major principles upon which such a scientific analysis must be based are: (1) the fate and biological activity of a compound are determined by the chemical properties of the compound; (2) compounds do not show adverse effects below certain threshold concentrations, and the magnitude of response is related to dose; (3) inherent metabolic processes allow organisms to accommodate low doses of chlorinated organic chemicals; (4) observations associated with the presence of a certain compound must be biologically plausible effects, based on the specificity of the compound's activity in experimental systems. With respect to the first of these principles, there is abundant scientific evidence that the physical and chemical properties of chlorinated organic chemicals govern their bioaccumulative potential, toxicological properties, and thus their potential behavior and effects in the environment. Chemicals that have low solubility in water are highly lipophilic and have low vapor pressure, tend to accumulate in biological systems, and degrade slowly in the environment. Chlorinated organic chemicals that possess these characteristics include those having a carbon ring structure and multiple chlorine substitution. Other chlorinated organic chemicals with lesser degrees of chlorine substitution, such as 2,4-dichlorophenoxyacetic acid (2,4-D), trichlorophenol, chloroform, and dichloroethane, do not share the physical and chemical properties of the high molecular weight, cyclic, polychlorinated compounds and, as such, do not have the same potential to bioaccumulate. These differences among chlorinated organic chemicals with respect to their physical and chemical properties and behavior in the environment preclude the generalization that all organic chemicals containing chlorine behave similarly in the environment and act as persistent, bioaccumulative chemicals. The reactivity of chlorinated organic chemicals and hence their potential to produce biological effects depends on their specific molecular features. The substitution of chlorine into an organic molecule may increase or may reduce its biological activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetics of methylmercury in the blood of monkeys (Macaca fascicularis).

Statistical analysis of the blood mercury profiles of groups of two and four adult female cynomolgus monkeys (Macaca fascicularis) given single oral doses of 500 micrograms and 50 microCi (25.3 micrograms) methylmercury/kg body wt, respectively, indicates that a two-compartment model best describes the absorption and elimination of methylmercury in blood. Absorption was largely complete within 6 hr, and the half-time of methylmercury during the terminal elimination phase ranged from 10 to 15 days. In addition, three groups of five adult female cynomolgus monkeys were dosed with methylmercury every Monday, Wednesday, and Friday for periods up to 2 years at effective doses of 10, 25, or 50 micrograms methylmercury/kg body wt/day. The average blood levels at steady state were estimated to be 0.27 +/- 0.02, 0.69 +/- 0.03, and 1.51 +/- 0.08 ppm, respectively, with average time taken to achieve 95% of the steady-state blood level being about 92 days. The steady-state blood levels obtained via extrapolation of the results from the two single-dose experiments were significantly different from those actually achieved, indicating that the average steady-state blood levels under chronic dosing conditions may not be accurately estimated on the basis of short-term experiments. The data were also used to examine the impact of different dosing intervals on variation in blood mercury levels.

Whole-body retention, excretion and metabolism of [74As]arsenic acid in the hamster.

In order to assess the whole-body retention, excretion and metabolism of inorganic arsenic, male and female hamsters were given either a single oral or i.v. dose of 74As (congruent to 33' microCi/hamster; 0.01 micrograms arsenic/hamster) as arsenic acid. 74As radioactivity was measured in the whole body, urine and feces for up to 35 days. 24-h samples of urine were analyzed for arsenic metabolites. For the i.v. dosed hamsters, the half-period of elimination for the first component (65% of the dose) was 0.40 days; the second component (35% of the dose) had a half-period of 4.5 days. For the orally dosed hamsters, the half-period of elimination for the first component (98% of the dose) was 0.29 days; the second component (2% of the dose) had a half-period of 3.8 days. Differences in the percent of dose excreted between oral and i.v. dosed hamsters appeared to be due to the increased fecal excretion of arsenic (70%) in the orally dosed hamsters as compared to the i.v.v dosed hamsters (6%). No statistically significant differences between the i.v. and oral treatments were found in the half-periods of elimination for either of the 2 components. Analysis of the urine for metabolites revealed arsenic was present as dimethylarsinic acid and inorganic arsenic.

Neonatal low-level lead exposure in monkeys (Macaca fascicularis): effect on two-choice non-spatial form discrimination.

Monkeys were dosed orally with 500 microgram/kg/day of lead as lead acetate from day 1 of life. No overt signs of lead toxicity were observed. At 2--3 years of age they were tested on a two-choice non-spatial form discrimination using a WGTA apparatus. Treated monkeys showed deficits compared to controls on a series of 20 discrimination reversals; there was no difference between the groups in the effect of a series of "overtraining" trials introduced between reversals.

Neurotoxic response of infant monkeys to methylmercury.

Four infant monkeys were dosed orally with 500 microgram Hg/kg body wt./day /as methylmercury (MeHg) chloride dissolved sodium carbonate) beginning at 1 day of age. Neurological and behavioral signs of MeHg toxicity and blood Hg levels were monitored weekly. At first sign of MeHg intoxication, dosing with MeHg was terminated and the infants were monitored to assess reversal of the signs of MeHg toxicity. The first signs of MeHg toxicity, exhibited as a loss in dexterity and locomotor ability, were observed after 28--29 days of treatment; the blood Hg levels were 8.0--9.4 microgram Hg/g blood. Dosing was terminated at 28--29 days of treatment but the signs of MeHg toxicity continued to develop. The infants became ataxic, blind, comatose and were necropsied at 35--43 days after initiating treatment with MgHg. The mercury concentrations in tissues analyzed after necropsy were highest in liver (55.8 +/- 3.2 microgram Hg/g) followed by occipital cortex (35.6 +/- 4.8 microgram Hg/g) renal cortex (32.8 +/- 1.6 microgram Hg/g). The frontal and temporal cortices had 27.0 +/- 3.4 and 29.6 +/- 4.9 microgram Hg/g respectively while the cerebellar Hg concentration averaged 13.0 +/- 1.5 microgram Hg/g. The mean blood/brain ratio was 0.21 +/- 0.4. Histopathologic lesions were marked in the cerebrum with less severe lesions in the cerebellar nuclei. The Purkinje and granular cells of the cerebellar vermis appeared histologically normal. Lesions were not observed in the peripheral nervous system. The signs of MeHg intoxication, the tissue distribution of MeHg and histopathologic lesions observed in the infant monkeys were similar to those reported for adult monkeys.

Tissue distribution as a factor in species susceptibility to toxicity and hazard assessment. Example: methylmercury.

Data on the tissue distribution and pharmacokinetics of methylmercury(MeHg) in cats and humans were utilized as an example of how such data can assist in extrapolating toxicity data between animal species. These data demonstrate that the whole-body half-time for clearance of MeHg was the same for cats (76.2 +/- 1.6 days) and humans (78 +/- 5 days) and that the concentration of MeHg in the brain at comparable signs of toxicity were the same (10 ppm) in the two species. However, the blood:brain ratio of MeHg concentration was 10 times as high in cats (1:1) as humans (1:10). From these data it was hypothesised that the no-effect level of methylmercury intake in cats should be 10 times that for humans. This hypothesis was verified from data o MeHg toxicity in cats and humans which demonstrated that ataxia developed in cats at a minimum dose of 46 microgram MeHg/kg body wt/day with blood MeHg levels of 6 to 8 ppm; humans developed ataxia with blood MeHg levels of 0.6 to 0.8 ppm and an estimated intake of 4 microgram MeHg/kg body wt/day.

Retention and tissue distribution of 210Pb (NO3)2 administered orally to infant and adult monkeys.

The retention and tissue distribution of 210Pb were studied in 10-day-old, 150-day-old, and adult monkeys. Lead-210 nitrate was administered to the monkeys by gavage after a 12 hr fast and 210Pb excreted in urine and feces was monitored for 96 hr. All monkeys were necropsied 96 hr after dosing and the 210Pb concentrations of various tissues was determined. The data demonstrated that infant monkeys retained 64.5 and 69.8% of the orally administered 210Pb at 10 and 150 days of age, respectively, while adult monkeys retained 3.2% of the 210Pb dose. Blood 210Pb levels 96 hr after dosing did not vary significantly between age groups. Of the 210Pb contained in blood, 98-99% was found in blood cells and 1-2% in blood plasma; 5-8% of the Pb in blood cells was bound to blood cell membranes. None of these parameters varied significantly with age. The percentage of the lead dose excreted in urine did not vary significantly between age groups. Analysis of tissues for 210Pb revealed that both the tissue Pb concentrations and tissue Pb:blood Pb ratios were significantly higher in the bone structure of infants than adults. Brain Pb:blood Pb ratios were significantly greater in 10-day-old infants than 150-day-old infants or adults.

Nursery rearing of infant monkeys (Macaca fascicularis) for toxicity studies.

At birth, nine infant male cynomolgus monkeys (Macaca fascicularis) weighed an average of 402 g and 16 infant female cynomolgus monkeys weighed an average of 362 g. Both female and male infants last 15-20 g by the fourth day after birth. Female and male infants showed a growth rate of approximately 4 and 5 g body wt/day, respectively, from 4 to 150 days of age. Caloric intake increased from approximately 140 cal/gkg body weight/day in both females and males on the first day after birth to peak values of 325 and 290 cal/kg body weight/day in females and males, respectively, and subsequently declined to about 200 cal/kg/day in males and 250 cal/kg/day for females. Total calories consumed per day increased from 53 cal/day in females and 68 cal/day in males to approximately 200 cal/day after 60 days of age in both females and males. Erythrocyte counts, packed cell volume, and hemoglobin values decreased from birth to 2 weeks of age, then stabilized. An increase in lymphocyte count, with a concomitant decrease in mature neutrophils, was observed from birth to 6 weeks of age. "Temper fits" and certain aggressive behavioral signs were observed as early as 3-4 days after birth, and infants began to develop social orders as early as the 30-40th day. Behavioral abnormalities frequently seen in infants reared in isolation were not observed.

Chronic toxicity of methylmercury in the adult cat. Interim report.

Doses of 3, 8.4, 20, 46, 74 or 176 mug Hg/kg/day were fed to groups of 8--10 adult cats, either as methylmercuric chloride or as methylmercury-contaminated fish, 7 days/week for up to 2 years. Food consumption, body weight change, blood mercury levels, haematology, urine analysis, serum blood urea nitrogen (BUN) levels and neurological status were assessed regularly in all animals. Clinical signs of methylmercury toxicity -- consisting of ataxia, loss of balance and motor incorrdination -- occured in groups receiving 176 mug Hg/kg/day after 14 weeks of treatment. Pathological findings were confined to the nervous system and consisted of loss of nerve cells with replacement by reactive and fibrillary gloisis. Terminal blood and brain mercury levels were approx. 10 ppm. There were no differences in the time required to develop clinical signs of methylmercury toxicity, tissue mercury levels or pathology between the groups of cats receiving methylmercury as methylmercuric chloride or as methylmercury-contaminated fish, at either dose level. Blood mercury levels in the remaining doses groups appeared to plateau after 40 weeks of treatment. Groups receiving 46 mug Hg/kg/day began to show some neurological impairment after 60 weeks of treatment which did not progress in subsequent weeks. No treatment-related effects were present in groups receiving 20, 8.4 or 3 mug Hg/kg/day after 2 years.

Action of several -adrenoceptor blocking drugs in the pregnant sheep and foetus.

1. The effect of several beta-adrenoceptor blocking drugs on the pregnant ewe and foetus were studied. Bunolol, butidrine, oxprenolol, propranolol and USVP65-24 all crossed the ovine placenta and produced a beta-adrenoceptor blockade in the ovine foetus. AH3474, AY21011 and sotalol did not cross the ovine placenta as assessed by the absence of a beta-blockade in the foetus when these compounds were administered to the pregnant ewe.2. Of the beta-blocking compounds tested, only propranolol and oxprenolol produced a prolonged blockade in the foetus. The beta-blockade with propranolol was of 3 h duration in the ewe and 10 h duration in the foetus. Oxprenolol produced a beta-blockade of 3 h duration in the ewe and 8 h in the foetus.3. The beta-blocking drugs which did cross the ovine placenta were more soluble in organic solvents (ether, chloroform, corn oil and olive oil) than those which did not cross the ovine placenta.