Relation of Lake Ontario fish consumption, lifetime lactation, and parity to breast milk polychlorobiphenyl and pesticide concentrations.

Lactating female members and spouses of male members of the New York State Angler Cohort who agreed to provide breast milk samples were the subjects of this study. Questionnaires were provided to participants focusing on Lake Ontario fish consumption, reproductive history, and lactation history. Milk samples were analyzed for 77 polychlorinated biphenyls (PCB) congeners, 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (DDE), a metabolite of dichlorodiphenyltrichloroethane (DDT), hexachlorobenzene (HCB), and 1,1a,2,2,3,3a, 4,5,5,5a,5b,6-dodecachlorooctahydro-1,3, 4-methano-1H-cyclobuta[cd]pentalene (Mirex). The percentage of samples with quantifiable levels, above the limit of detection (LOD), varied among the individual congeners from 10 to 100%. Nine PCB congeners (designated by their IUPAC No.) and DDE were found in all of the 100 samples analyzed. These include the following, in decreasing order of concentration: DDE>153>138>180>118>187>188>177>200. Total PCB concentrations were estimated by taking the sum of the concentrations of all PCB congeners (up to 77 congeners) above their respective LOD in a given sample. PCB concentrations increased with increasing concentration of milk lipid. Lipid adjusted PCB concentrations increased as a function of maternal age. PCB congener profiles in milk favored the higher chlorinated congeners, with the four highest congeners having 5 to 7 chlorine atoms. Fish eaters had a significantly higher level of several major PCB congeners with congeners 153 and 138 being 1.36 and 1.34 times higher, respectively. PCB and DDE concentrations, expressed on a lipid basis, varied inversely with parity. The total number of months of lifetime lactation varied inversely with the total PCB concentration in breast milk. A similar relationship was evident for DDE. These data are of use for risk assessment in estimating the relative exposure to these environmental contaminants in breast fed infants whose mothers consumed contaminated Lake Ontario fish.

Comparison of PCB congeners and pesticide levels between serum and milk from lactating women.

Samples of blood and milk were obtained from lactating women participating in the New York State Angler study. A total of seven women gave one blood and one milk sample at time intervals between blood and milk collection different for each woman. The time between samples varied from 3 to 318 days. One subject provided a second milk sample 219 days after the first milk sample. The samples were analyzed for 69 PCB congeners, DDE (a metabolite of DDT), Mirex, and hexachlorobenzene (HCB). Lipid content was determined by gravimetric analysis. The congener profiles in serum and milk were similar for each individual but different among all subjects. The sum of the concentrations of the congeners present above the limit of detection was used to estimate the total PCB concentration that was in the range of 2.6 to 5.8 ng/g of serum and 3.5 to 14.1 ng/g of milk. The ratio of serum to milk concentrations varied from 0.18 to 1.66 with a mean of 0.65+/-0.49 showing no consistency among individuals prior to adjusting the data for lipid content. The total PCB levels normalized for lipid content were 320-728 ng/g of serum lipid and 239-428 ng/g of milk lipid. The range of the lipid adjusted serum/milk ratio was 1.1 to 2.8 and the mean+/-SD serum/milk ratio was 1.9+/-0.5. The ranges of lipid adjusted serum concentration of DDE, HCB, and Mirex were 95 to 591, 8 to 48, and 3 to 29 ng/g lipid, respectively. The ranges of lipid adjusted milk concentration of DDE, HCB, and Mirex were 90 to 577, 11 to 22, and 1 to 10 ng/g lipid, respectively. For DDE, HCB, and Mirex, the means of the individual lipid adjusted serum to milk ratios were 1.5+/-0.7, 2.5+/-1.5, and 5. 3+/-4.6, respectively. Considerable differences were found among lipid adjusted concentrations of these environmental pollutants in serum and milk samples from the same individual. This suggests that body burden estimates in lactating women using different matrices may not be equivalent even when lipid adjusted values are used.

Standardization of a method for the routine analysis of polychlorinated biphenyl congeners and selected pesticides in human serum and milk.

A methodology is presented for the routine determination of specific polychlorinated biphenyl (PCB) congeners in serum and milk samples. The procedures include standardized extraction, cleanup and quantitation by high-resolution gas chromatography (GC) and comprehensive quality assurance program to minimize systematic and erratic errors. The analyses of 68 PCB congeners and three pesticides, p,p1-dichloro diphenyl dichloro ethylene (DDE), hexachlorobenzene (HCB), and Mirex, at part-per-billion levels include the addition of surrogate congener standards (IUPAC isomers #46 and #142), extraction with hexane after protein precipitation, cleanup with Florisil, and analysis by GC with capillary column and electron capture detection. Quantitation is based on calibration standards and response factors using isomers #30 and #204 as internal standards. The quality control activities consist of analyses of samples in batches of 6 to 10 simultaneously with quality control (QC) samples. The quality assurance program checks that the procedures are under control by the use of control charts and set the criteria for data acceptability. The detection limits for the congeners and pesticides associated with the analyses of 500 serum samples and of 100 milk samples are reported. In addition, typical profiles of congener distribution in both matrices are illustrated.

Extracorporeal regional complexing haemodialysis treatment of acute inorganic mercury intoxication.

A 70-year-old white female presented approximately 24 h after ingesting three 475 mg tablets (1.425 g) of mercuric chloride in a suicide attempt. Acute renal failure necessitated the initiation of haemodialysis approximately 4 d after the ingestion. Treatment with BAL (2,3-dimercaptopropanol) resulted in only small increases in mercury output into dialysate. A new procedure involving the extracorporeal infusion of the chelating agent dimercaptosuccinic acid (DMSA) into the arterial blood line during haemodialysis was initiated. This procedure of Extracorporeal Regional Complexing Haemodialysis (ERCH) had been effective in increasing methylmercury removal in patients poisoned by contaminated grain. The first DMSA-ERCH procedure was performed 6 d after poisoning. There was a dramatic increase in mercury output into the dialysate. During three treatment sessions of 80 min each, 1189 micrograms of mercury were removed from the patient. The dialysed mercury represented the only mercury output since the patient was anuric and not producing faeces. DMSA-ERCH appears to be much more effective than BAL and haemodialysis in the treatment of acute inorganic mercury poisoning. The long interval between poisoning and initiation of treatment probably contributed to the patients ultimate demise, 28 d after poisoning. Efficacy of the DMSA-ERCH procedure for inorganic mercury poisoning is likely to be improved as the interval between exposure and treatment is reduced.

Influence of cefoperazone on ethanol and acetaldehyde metabolism in vitro.

The effect of cefoperazone on ethanol and acetaldehyde metabolism was studied in rat liver homogenates and with a purified aldehyde dehydrogenase. Rat liver homogenates were incubated with ethanol (30 mM) alone or in combination with cefoperazone (15 or 150 micrograms/g liver). Ethanol and acetaldehyde concentrations were determined at 6, 12, 18 and 24 minutes. Cefoperazone added to the incubation medium inhibited ethanol and acetaldehyde metabolism in a concentration-dependent manner. The addition of cefoperazone to rat liver homogenates incubated with acetaldehyde (300 microM), however, did not inhibit acetaldehyde disappearance for a period of 15 minutes. Purified aldehyde dehydrogenase was incubated with 300 microM acetaldehyde. When cefoperazone was added, acetaldehyde disappearance was significantly slower than without cefoperazone. The data indicate that cefoperazone inhibits ethanol metabolism in rat liver homogenates in a concentration-dependent manner. The effect of the antibiotic on acetaldehyde elimination in liver homogenate, however, depends on the concentration of acetaldehyde in the medium. The acetaldehyde dehydrogenase obtained from yeast is inhibited by cefoperazone.

Alcohol consumption and systolic blood pressure in the general population.

Survey data was analyzed to examine the relationship between alcohol consumption and systolic blood pressure (SBP) in the general population. Among older people, SBP is higher for heavier drinkers. Among females, SBP is slightly lower for the light drinkers than for abstainers.. These effects are measured with obesity, race, and menopause, use of birth control pills, smoking, and anxiousness held constant. The reasons for these effects are not clear.

Ethanol and indomethacin interactions in motor impairment, hypnosis, and body temperature.

The actions of indomethacin on the effects produced by ethanol were determined in rats and mice by measuring motor coordination (Rotorod test), sleep times, and body temperatures. Mice receiving indomethacin in combination with ethanol slept shorter times than those receiving ethanol alone. The blood and brain ethanol concentrations at time of awakening were significantly higher in the mice receiving the combination of drugs. Ethanol actions on motor impairment in rats and mice and on hypothermia in mice were not altered by pharmacologically relevant doses of indomethacin. The data show that indomethacin antagonizes only some of the observed effects of ethanol. It is suggested that a common mechanism, such as prostaglandin synthesis, is not involved in the interactions of both drugs.

Drug interactions in goldfish tolerant to ethanol and pentobarbital.

The interactions between short- and long-term exposure to ethanol and pentobarbital were characterized in goldfish tolerant to one of these drugs. The effects of ethanol and pentobarbital were measured by the overturn test as the time of onset of the loss of the righting reflex and the corresponding drug concentration in brain of fish immersed in 674 mumol/ml ethanol or 1.21 mumol/ml sodium pentobarbital (challenge solutions). The chronic treatment consisted of 6- or 24-h preexposure to 130 mumol/ml ethanol or 0.06 mumol/ml sodium pentobarbital in Tris buffer solution. Fish preexposed to ethanol for 6 or 24 h or to pentobarbital for 24 h were rendered more tolerant to pentobarbital or ethanol, respectively. Preexposure to pentobarbital for 6 h, however, produced in goldfish the same degree of tolerance to ethanol and to pentobarbital.

Ethanol and diazepam effects on intrauterine growth of the rat.

Four groups of 6 pregnant Long-Evans rats were intubated on days 6, 7, 9, 12, 15, and 18 of gestation with (a) 4 g/kg ethanol (E), (2) 10 mg/kg diazepam (D) plus isocaloric amounts of sucrose, (3) 10 mg/kg diazepam plus 4 g/kg ethanol (DE), and (4) gum arabic suspension plus sucrose solution in isocaloric amount with E (PF). All groups were pair-fed with group DE and had ad libitum access to water. On day 19 there were no differences in maternal weight gain, litter size, fetal weight, and protein content in fetal brain. Fetal brain and placental weight were significantly decreased in E, D, and DE. The decrease in placental weight in DE was significantly higher than in E or D. The concentrations of glutamic acid, alanine, glycine, serine, threonine, leucine, valine, and tyrosine in fetal brains were significantly decreased after E and D, but not different in DE from PF. Diazepam did not potentiate the effects of ethanol. Undernutrition could be a confounding factor in the observed effects.

Indomethacin-ethanol interactions on acute inflammation.

The effect of ethanol on the anti-inflammatory actions of indomethacin was studied using carrageenan-induced edema in the paw of the rat as the test for acute inflammation. The agents were administered 1 hour prior to carrageenan injection, and the volume of the paw was measured immediately and at 3 and 5 hours after carrageenan. Ethanol at 1, 2, and 4 g/kg and indomethacin at 5 and 20 mg/kg significantly inhibited paw edema at 3 and 5 hours. The combination of the various doses of ethanol and indomethacin produced the same degree of inhibition as ethanol alone and significantly higher inhibition than indomethacin alone. The concentration of indomethacin in the inflammed paw was significantly higher than in the other paw in animals receiving 20 mg/kg indomethacin alone and 5 or 20 mg/kg indomethacin in combination with 2 g/kg ethanol. Ethanol co-administration significantly increased the concentration of indomethacin in the inflammed paw. Whether the observed interaction is due to increased concentration of indomethacin at the site of action or to direct interaction of ethanol and indomethacin in the inflammation process remains unclear.

Alcohol-chlordiazepoxide interaction.

The effects of chlordiazepoxide (CDP) or its N-demethyl metabolite (NDCDP) on ethanol-induced sleep time were investigated. The results indicate that CDP or NDCDP produced a supra-additive effect on the duration of sleep time induced by ethanol. These effects were not due to an alteration in the rate of elimination of blood ethanol levels. Mice which were administered CDP/ethanol had significantly higher blood and brain CDP levels than mice injected with CDP alone. The increase in CDP concentrations could be partly responsible for the supra-additive prolongation of ethanol sleep time. Our results also indicate that NDCDP and/or its metabolites were largely responsible for the supra-additive effect, because mice injected with CDP/ethanol or NDCDP/ethanol (ethanol 4 g/kg: CDP or NDCDP, 10 mg/kg) showed comparable increases in sleep time, and the blood and brain levels of NDCDP were comparable in these two groups.

Placental and fetal composition during the last trimester of gestation in the rat.

The composition of rat placentae or fetuses at Days 14, 17, and 21 of gestation and of 1-day-old pups was determined by measuring water, lipid, nonlipid, inorganic substances, and free amino acids. Placental weight significantly increased (P less than 0.05) from Day 14 to Day 21. The concentrations of amino acids in the placenta were as follows: 1) glutamic and aspartic acids decreased as gestation proceeded; 2) leucine, phenylalanine, tyrosine, and isoleucine reached a minimum on Day 17, while there were no differences between Days 14 and 21; 3) glycine, methionine, and phosphoserine attained a maximum on Day 14, followed by lower and constant concentrations on Days 17 and 21; and 4) serine, lysine, threonine, ethanolamine, valine, arginine, and ornithine remained constant. Fetal weight increased significantly (P less than 0.05) during the last week of gestation; no changes in body weight were observed from Day 21 of gestation to 24 h after birth. Fetal water concentration decreased significantly (P less than 0.05) and nonlipid concentration increased significantly (P less than 0.05) as gestation progressed; after birth, increased lipid and decreased water contents were observed. The concentration of each amino acid in the fetuses increased significantly (P less than 0.005) as gestation advanced except for alpha-aminobutyric acid which significantly decreased (P less than 0.001). There were no differences in the concentrations of amino acids between Day 21 fetuses and 1-day-old pups. The total amount of free amino acids in the rat fetuses increased significantly (P less than 0.001) after Day 17 of gestation. The measured changes in placental weight and composition were not correlated with the observed changes in the fetus. The amino acids measured at term in the rat placentae were present in the same relative amounts as reported for human placentae.

Ethanol-induced prenatal growth deficiency: changes in fetal body composition.

Ethanol (6 g/kg/day) produced intrauterine growth retardation (both body weight and length) in rat fetuses compared to pair-fed controls. Associated with this retardation was an increase in fetal body water and sodium content and a decrease in lipid-free solid content. Comparable electrolyte changes were not observed in maternal blood. These effects in fetal body content are not commonly observed in fetal malnutrition studies and are suggestive of a direct teratogenic effect of ethanol.

Influence of lactation on rate of disappearance of ethanol in the rat.

The rate of blood ethanol disappearance was significantly increased in lactating rats compared to virgin controls and parturient rats that had their offspring removed in birth. Liver but not kidney size was also increased in lactating rats.

Electrolyte composition of fetuses, placentas, and maternal plasma during the last trimester of gestation in the rat.

Pregnant rats were sacrificed during their last trimester of pregnancy. Maternal plasma levels of calcium and zinc decreased during gestation, whereas calcium and zinc levels increased in fetuses as gestation progressed. Although sodium and potassium levels remained relatively constant in maternal plasma, the levels of these electrolytes in fetuses decreased with gestation. Magnesium levels remained relatively unchanged in both maternal plasma and fetuses. The changes in placenta electrolyte content resembled the pattern of changes in fetuses.

Development of functional tolerance to pentobarbital in goldfish.

The acute effects of pentobarbital were measured by the times required for the loss of righting reflex (overturn point) and the pentobarbital brain concentration associated with the overturn. The test consisted of immersing the fish in a 0.3 mg/ml sodium pentobarbital in 0.1 M Tris buffer challenge solution until the overturn point was reached. To examine the development of tolerance the fish were pre-exposed to 0.1 M Tris buffer solutions containing 0.0, 0.010, 0.015 and 0.025 mg/ml of sodium pentobarbital for 6, 24 or 48 hr at which time the overturn times and the pentobarbital brain concentrations at overturn in the challenge solution were determined. The mean pentobarbital content in the brain at overturn of fish pre-exposed to 0.015 or 0.025 mg/ml solution was significantly higher (P less than .01) than in control fish. The loss of tolerance was determined at 3 hr after termination of the pre-exposure of the fish to the various pentobarbital solutions; tolerance was measured only in the group of animals pre-exposed to the 0.025 solution by the significant increase (P less than .01) in the pentobarbital brain levels over control fish. The equilibration curve for fish swimming in 0.025 mg/ml of sodium pentobarbital was determined for 48 hr. A steady state was attained within 6 hr with brain levels that reached approximately 80% the concentration of the external solution.