Effect of ketamine on cocaine-induced immunotoxicity in rats.

The abuse of cocaine (COC) with ketamine (KET) is currently popular among young drug abusers and has been associated with increased risk of human immunodeficiency virus (HIV) infection. The effect of subacute exposure to COC and KET alone and in combination on the immune system was assessed in adult male Sprague-Dawley (SD) rats. To simulate the route and mode of human exposure, rats were treated with COC alone (5 mg/kg, i.v.), KET alone (100 mg/kg, p.o.) or KET followed immediately by COC (same doses and routes of administration) once-a-day for 7 consecutive days. Rats were sacrificed 30 minutes following the last treatment. Total circulating leukocyte and lymphocyte counts were decreased with relative neutrophilia, whereas immunoglobulin M (IgM) antibody response to sheep erythrocytes (SRBCs) was increased in animals treated with COC. Moreover, treatment with COC alone increased serum interleukin-10 (IL-10) concentration; however, it did not affect serum interferon gamma (INF-gamma) concentration. Spleen histology showed hyperplasia of white pulp whereas thymus gland demonstrated mild cortical degeneration. On the other hand, KET treatment did not produce any significant change of any of these parameters. However, when coadministered with COC, significant reduction of bodyweight, spleen/bodyweight, and thymus/bodyweight ratios with degeneration of splenic white pulp and thymic cortex occurred. Moreover, the primary immunoglobulin response to SRBC and serum IL-10 concentration were decreased without significant change in serum IFN-gamma or circulating leukocytic counts. COC caused a significant increase in serum corticosterone concentration that KET effectively prevented. On the other hand, a significant increase in plasma and tissue concentrations of norcocaine (NC) resulted following KET and COC administration in combination. Daily SKF-525A pretreatment at a dose of 30 mg/kg, i.p., for 7 days 1 hour prior to KET and COC in combination effectively reversed the effects of this combination on body weight, organ/bodyweight ratios, histopathology, and serum IgM and IL-10 concentrations without affecting leukocytic counts. On the other hand, SKF-525A pretreatment did not change the immunomodulatory effects of COC compared to non-pretreated animals. The results suggest that COC-induced immunomodulation most likely occurred through neuroendocrinal mechanisms. On the other hand, enhanced oxidative metabolism of COC in the presence of KET-induced immunosuppression.

In vitro penetration of soil-aged mercury through pig skin.

The dermal bioavailability of mercury "aged" in soil for 3 mo was compared to that of pure mercury (without soil) and to mercury in brief contact with soil (16 h). Studies were conducted in vitro with [203Hg]mercuric chloride on dermatomed male pig skin by flow-through diffusion cell methodology. Less than 0.5% of the initial mercury dose penetrated through skin into receptor fluid after each treatment. The majority of pure mercury became covalently bound to skin. However, a short contact time with either an Atsion (sandy) or Keyport (clay) soil significantly decreased the total penetration of mercury (sum of receptor fluid and skin) by 40%. After aging, a 95% reduction in total penetration was observed for the compound relative to chemical without soil. Both soils bind mercury more strongly with time, as evidenced by larger quantities of radioactivity in soil and smaller amounts in skin decontaminate after aging than in soil for 16 h. Decreased mercury bioavailability with aging indicates lower health risk and reduced need for soil cleanup.

Developmental immunotoxicity of cocaine and ethanol in postnatal Lewis rats.

The immunomodulatory effect of cocaine (COC), ethanol (EtOH) and their combination was investigated in the developing immune system of postnatal Lewis rats. To simulate the route of exposure during lactation, newborn rats were orally treated with either saline, 20 mg COC/kg, and 0.6 g EtOH/kg or the coadministration of COC and EtOH from day 1 to 21 of life. Rat pups were sacrificed thirty minutes following the last treatment. Total lymphocytes and spleen/body weight ratios were decreased in animals exposed to COC. These immunotoxic effects were not enhanced by the coadministration of EtOH. However, pups exposed to both drugs had significantly decreased levels of serum immunoglobulin M (IgM) when compared to saline-treated rats. Plasma and tissue distribution studies revealed that the combination treatment group had a higher COC content in the brain and spleen as well as an increase in the metabolites benzoylecognine (BE) and norcocaine (NC) in the spleen. Ethylcocaine (EC) formation was not demonstrated in this model.

Effect of sub-chronic cocaine and lidocaine exposure on the lymphoid tissues in neonatal rats.

Illicit cocaine varies in purity and is often adulterated with local anesthetics such as lidocaine. Chronic cocaine exposure is associated with immunological modulation in humans and animal models. The effect of sub-chronic oral exposure to cocaine (COC) and lidocaine (LIDO) alone and in combination on the lymphoid organs was assessed in neonatal rats. Lewis rat pups were orally administered saline (SAL), COC, LIDO or both drugs in combination, 20 mg/kg each, from birth to day 21. Statistically significant (P < 0.05) decreases in lymphocyte and total leukocyte levels as well as decreases in spleen weight were observed in pups treated with COC alone. LIDO alone did not affect these parameters in comparison to SAL treated controls. Rats receiving COC and LIDO did not display a significant reduction in spleen weight or in the blood cell populations studied. However, rats treated with COC and LIDO in combination had significantly decreased serum immunoglobulin M (IgM) concentration. Quantitative plasma and tissue analyses ascertained the concentrations and tissue disposition of each drug following oral administration. The results suggest that the effect of COC on the lymphoid tissues and white blood cell parameters is modified in the presence of LIDO in the developing rat.

Comparison between oral and dermal bioavailability of soil-adsorbed phenanthrene in female rats.

Phenathrene is a major coal tar component found in hazardous waste disposal sites. The purpose of this study was to evaluate the extent to which phenanthrene adsorption to either of 2 different soils affects the manner in which phenanthrene is subsequently handled in orally and dermally exposed adult female rats. Absorption from the gastrointestinal tract was relatively rapid for all treatments with maximum plasma concentration of radioactivity occurring within 1 h following oral administration. After dermal application, the time to reach maximum plasma concentration (12 h) was the same in all 3 phenanthrene treatment groups although sandy soil lowered the area under the plasma concentration time curve (AUC) compared to the pure and clay soil groups. Dermal exposure increased absorption half-lives 8-fold compared to oral exposure in the pure group and 15-fold in each of the soil groups. After oral or dermal treatment with phenanthrene alone or adsorbed to soil, the urine represented the primary excretion route of 14C activity. Ileum contained the highest tissue concentration of radioactivity in all oral treatment groups. However, the skin application site contained the highest concentration of radioactivity followed by ileum after dermal exposure. Phenanthrenequinone and 9,10-phenanthrene dihydrodiol were the major urinary metabolites detected in the 0-12-h urine of all treatment groups in both routes of administration. The data suggest that the oral exposure route for phenanthrene is a greater health risk than the dermal route. However, the presence of sandy or clay soil tends to delay the elimination of phenanthrene from the plasma.

Electron microscopic study on the effect of alternate-day hydrocortisone therapy on lymphocyte populations in rat spleen and lymph nodes.

The ultrastructural effects of 400 mg/M2/day of hydrocortisone sc, given alternatively from day 7 through day 19, were studied on the lymphocyte populations in the white pulp of the spleen and in the cortex of the mesenteric lymph nodes of the immunologically immature rat. Results were consistent with both a direct lytic effect of hydrocortisone on small lymphocytes of the nodular cortex of the mesenteric lymph nodes and an indirect effect on small lymphocytes of the periarterial lymphatic sheath (PALS) of the spleen supplied via the thymus. In contrast, medium-sized lymphocytes in the PALS appeared to be unaffected by hydrocortisone, while medium-sized lymphocytes of the nodular cortex of the mesenteric lymph nodes exhibited a temporary depletion of cytoplasmic organelles. Hydrocortisone appeared to depress protein synthesis in these latter cells. The decrease in numbers of lymphoblasts and plasmablasts observed in the nodular cortex of the mesenteric lymph nodes and the white pulp of the spleen is consistent with hydrocortisone interference with proliferation and differentiation of activated B cells.

A comparative study of the kinetics and bioavailability of pure and soil-adsorbed naphthalene in dermally exposed male rats.

The aim of this study was to utilize pharmacokinetic techniques to assess the bioavailability of sandy or clay soil-adsorbed naphthalene vs chemical alone following dermal treatment of male rats. Animals were exposed to 43 micrograms total of 14C-naphthalene (pure or adsorbed to one of two soils) introduced into a shallow glass cap covering a 13-cm2 area on the skin of each rat. While both soils delayed the time to reach maximum plasma concentration of radioactivity and significantly increased the half-life of plasma absorption, only sandy soil significantly decreased the peak plasma concentration of radioactivity versus the pure compound. Within 12 h after dermal application, approximately 50% of the naphthalene dose was excreted in the urine of the pure and clay soil-adsorbed groups. However, when naphthalene was adsorbed to sandy soil, the percentages of the initial dose excreted in the urine collected between 0-12 h and 12-24 h were nearly equal (33-39%). Furthermore, sandy soil adsorption shifted the secondary excretion route from expired air to feces and significantly lowered the amount of radioactivity in expired air relative to naphthalene alone. In the presence of sandy soil, a significantly larger amount of radioactivity washed off of the skin application sites. In all groups the predominant urinary metabolites determined by high performance liquid chromatography were 2,7- and 1,2-dihydroxynaphthalenes.

Soil decreases the dermal penetration of phenol in male pig in vitro.

Skin is a primary route of exposure to phenol, a major chemical found in hazardous waste sites. The effect of soil adsorption on the dermal bioavailability of phenol was assessed by applying [14C]phenol alone (P) or with sandy (P-S) or clay (P-C) soil to dermatomed male pig skin samples in flow-through diffusion cells. Maximum penetration of P-S and P-C was significantly decreased by one-half and by two-thirds, respectively, compared to P. Furthermore, the penetration of phenol into receptor fluid and the amount bound to skin were significantly lower when phenol was adsorbed to either soil versus P. While less radioactivity penetrated skin with soil-adsorbed phenol treatment than P, significantly more radioactivity was loosely adsorbed to skin and could be easily washed off of the skin surface by soap and water. Only a small fraction (< 5%) of the chemical was metabolized by skin to hydroquinone and catechol in all treatment groups. The results of this study indicate that the bioavailability and thus the potential health risk from dermal exposure to phenol is reduced if the chemical is adsorbed to soil.

Effect of alternate-day hydrocortisone therapy on the immunologically immature rat. I: Effect on blood cell count, immunoglobulin concentrations, and body and organ weights.

The effect of 400 mg/M2/day of hydrocortisone, given alternatively from day 7 to day 19, was studied in the immunologically immature rat, a steroid-sensitive species. Animals, sacrificed 2 days following the completion of treatment, suffered from an underweight thymus and spleen, leucocytosis, and peripheral lymphocytopenia, probably not due to redistribution of lymphocytes from blood to tissues. In addition, a significant decrease in serum IgM concentration, reflecting a deficit in primary immune response, was evidenced. Although the percentage of lymphocytes returned to normal in rats sacrificed 23 days after treatment, an overweight thymus and spleen and persistent leucocytosis may reflect a compensatory overactivity of the developing immune system. In contrast, serum IgM concentration increased, but to a value less than normal. An indirect effect of hydrocortisone on lymphocytes through its action on thymus, as well as a direct effect on B cells, is suggested. Unlike humans, alternate-day steroid therapy delayed the normal growth pattern of rat, with a defective rate of growth only during the treatment period.

Effect of alternate-day hydrocortisone therapy on the immunologically immature rat. II: Changes in T- and B-cell areas in spleen.

The histologic effect of 400 mg/M2/day of hydrocortisone, given alternatively from day 7 to day 19 after birth, was studied on the spleen of the immunologically immature rat. Two days after the cessation of treatment, the periarteriolar lymphatic sheaths were found to be largely depleted of small lymphocytes. Immunoperoxidase studies confirmed a depletion of T lymphocytes. The effects of hydrocortisone on the thymus seem to be more important than its direct lymphocytolytic effect in producing this splenic lesion. In contrast, no apparent change in the number of medium-sized B lymphocytes in the marginal zone was detected. Medium-sized B lymphocytes of the spleen, reported to be responsible for IgM synthesis, appeared to be subjected to a different mechanism of hydrocortisone action, other than lysis, resulting in a decrease in antibody production. Primary follicles were not seen in spleens of hydrocortisone-treated rats. Twenty-three days after treatment, spleens had a histologically normal appearance.

Effect of alternate-day hydrocortisone therapy on the immunologically immature rat. III: Changes in T- and B-cell areas in lymph nodes.

The histologic effects of the alternate-day hydrocortisone therapy (400 mg/M2 from day 7 to day 19 after birth) were studied on the mesenteric lymph nodes of immunologically immature rats. In rats sacrificed 2 days following the cessation of therapy, depletion of lymphocytes of the thymus-independent area was apparent. Smaller lymphocytes were more susceptible to the effect of hydrocortisone than larger ones. The absence of primary follicles, normally present at this age, suggested a possible retardation in development of the immune system. B lymphocytes appeared to be the target of the direct lymphocytolytic effect of hydrocortisone. In rats sacrificed 23 days following the treatment, immunological maturity was achieved, indicating the reversibility of the hydrocortisone effect.

Sex differences in the bioavailability of soil-adsorbed m-xylene in orally exposed rats.

The bioavailability of soil-adsorbed m-xylene was assessed in male and female rats gavaged with an aqueous suspension of 14C-m-xylene alone or adsorbed to sandy or clay soil. Sex-related differences were observed in the rate and the amount of m-xylene-derived radioactivity absorbed and excreted in the presence of the soils. A higher peak plasma concentration of radioactivity was observed in females following treatment with sandy soil-adsorbed m-xylene. Further, sandy and clay soil-adsorbed chemicals demonstrated significantly longer absorption half-lives (t1/2), while sandy soil produced a shorter elimination t1/2 vs. m-xylene alone in female rats. Increased bioavailability of sandy soil-adsorbed m-xylene in females was evidenced by a significantly increased area under the plasma concentration time curve (AUC). Neither of the soils altered the maximum plasma concentration, the rate at which xylene-derived radioactivity was absorbed or eliminated, or the AUC in male rats. Fat contained the highest tissue concentration of xylene-derived radioactivity in all treatment groups of both sexes. Further, in all male and female treatment groups m-xylene was primarily metabolized and excreted in urine with methyl hippuric acid identified as the main urinary metabolite. Sandy soil slightly delayed urinary excretion in females while both soils increased expired air excretion in males compared to m-xylene alone. Methylhippuric acid was the main urinary metabolite in all groups.

Soil adsorption alters kinetics and bioavailability of trichloroethylene in orally exposed female rats.

Soil contamination with dangerous toxic chemicals remains one of the most difficult problems in this era. Bioavailability of a chemical absorbed through gastrointestinal tract exposure from contaminated soil may differ from that seen following exposure to the pure chemical. In this study 4.6 microCi of 14C-TCE (trichloroethylene) alone, or adsorbed to clay or sandy soil, was administered to female Sprague-Dawley rats. Maximum plasma levels of radioactivity were highest in the presence of clay soil. However, they were similar for TCE alone and sandy-soil-adsorbed chemical. The half-life (t1/2) of absorption was statistically longer and the half-life of elimination was statistically shorter in the presence of sandy soil compared with TCE alone. There were no differences in the area under the plasma concentration-time curves between groups. Liver and kidney exhibited the highest tissue concentrations of radioactivity in all groups. Urine was the primary route of excretion followed by expired air in the pure- and clay-soil-adsorbed groups. However, equal amounts of the dose were excreted in both urine and expired air of the sandy-soil-adsorbed group with a significant increase of radioactivity in expired air throughout the 72-h study period. Trichloroethanol was the major urinary metabolite of TCE.

Bioavailability of aspirin and salicylamide following oral co-administration in human volunteers.

BC powder (I) is a commercially available analgesic containing the active ingredients aspirin and salicylamide. The kinetics of I, BC powder minus aspirin (II), and BC powder minus salicylamide (III) were evaluated in 13 volunteers. Ten minutes after administration of I, aspirin reached a maximum concentration of 12.9 micrograms/mL, while salicylamide concentration reached a peak value of 3.4 micrograms/mL. However, when III was administered, aspirin was not detected at 10 min and only reached a concentration of 0.4 microgram/mL at 2 and 6 h. Furthermore, the area under the plasma concentration versus time curve for aspirin when III was administered was sixfold less compared with treatment with I. The area under the curve for aspirin metabolites was significantly different in I versus III. After treatment with II, a delay in salicylamide peak concentration was observed. Gentisamide was not detected throughout the study. This study demonstrates that salicylamide significantly enhances plasma levels of aspirin with potential therapeutic implications.

Differences in kinetics of pure and soil-adsorbed toluene in orally exposed male rats.

Assessment of health risk following exposure to chemically contaminated soil has primarily utilized results from studies conducted with pure chemicals. However, complex interactions with soil may alter the way in which a chemical subsequently interacts with the body. This study was conducted to determine if adsorption to either of two New Jersey soils qualitatively or quantitatively altered the way in which toluene is absorbed, distributed, metabolized or excreted by the body following oral exposure. Adult, male rats were gavaged with an aqueous suspension of 14C-toluene in the presence or absence of either an Atsion (sandy soil) or a Keyport soil (clay soil). Both soils reduced the peak plasma concentration of radioactivity, while sandy soil also reduced the time to reach peak vs toluene alone. Clay soil produced a statistically significant decrease in the half-life (t1/2) of elimination of radioactivity from plasma vs toluene alone. However, neither soil altered the area under the plasma radioactivity-time curve (AUC) vs toluene alone. Three-h post administration, stomach and fat contained the highest concentrations of radioactivity. No differences were detected in the tissue concentrations of radioactivity between the treatment groups. Urine was the primary excretion route of radioactivity in all treatment groups with lesser amounts excreted in expired air and negligible amounts in feces during the 48 h following exposure. Unmetabolized toluene represented greater than 98.8% of radioactivity in expired air of all treatment groups. Clay soil produced a statistically significant decrease in the excretion of radioactivity in expired air at the 0-1, 0-12, 0-24 and 0-48 periods vs toluene alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of soil on the dermal bioavailability of m-xylene in male rats.

Bioavailability of a chemical absorbed through the skin from contaminated soil may differ from that seen following exposure to the pure chemical. The objective of this research was to qualitatively and quantitatively assess the absorption, distribution, excretion, and metabolism of soil-adsorbed m-xylene versus pure m-xylene so that the potential for public health risk following dermal exposure could be evaluated. In this study a shallow glass cap covering a 13-cm2 area was fixed to the shaved skin of each male rat (6-10 rats per group) followed by the addition of 225 microliters of m-xylene containing 20 muCi of m-[14C]xylene alone or with one of two soils. Maximum plasma levels of radioactivity were highest for pure m-xylene while the values for the sandy and clay soil groups were approximately equal. Although clay soil statistically decreased the rate of absorption, the half-lives of elimination and the area under the plasma concentration time curve were not changed by either soil. The major route of excretion in the pure and sandy groups was via expired air followed by urine. However, in the presence of clay soil, the percentage of the initial dose in expired air was similar to that in urine. Forty-eight hours after treatment, skin application sites in both soil treatment groups contained amounts of radioactivity significantly higher than those of m-xylene treatment alone. In the presence of clay soil a statistical increase in m-xylene-derived radioactivity was also observed in fat beneath the treated skin area. Metabolite analysis by HPLC indicated that methylhippuric acid was the main urinary metabolite followed by xylenol and the parent compound in all groups.

Effects of soil on percutaneous absorption of toluene in male rats.

Previous assessments of health risks from soil-adsorbed chemical exposures relied on extrapolations from data derived with pure compounds. However, interactions between chemical and soil can alter the rate, amount, and form of chemical that enters the body, resulting in effects that are different from those that occur after exposures to chemical alone. In this study, male rats were treated dermally with [14C]toluene alone or adsorbed to either a sandy or a clay soil. Both soils produced a higher plasma concentration compared to pure toluene, with a statistical decrease in half-life of absorption observed after sandy soil-adsorbed treatment. The time to reach peak plasma concentration, half-life of elimination, and area under the plasma concentration-time curve (AUC) were similar for all groups. Skin and fat contained the highest concentration of radioactivity 48 h after all treatments. Pure and soil-adsorbed toluene were primarily metabolized and excreted via the kidney rather than exhaled. Furthermore, soil treatment did not alter the percentages of the metabolic products.

Soil adsorption alters bioavailability of benzene in dermally exposed male rats.

The potential for exposure to chemically contaminated soil is a concern for chemical industry and waste disposal site workers as well as for individuals living near the contamination site. Current assessment of potential health risks from these types of exposures relies almost exclusively on extrapolations from data derived with pure chemicals. Complex interactions with soil, however, may alter greatly the way in which a chemical subsequently interacts with the body. This study was conducted to determine if soil adsorption alters the way in which benzene, a common chemical contaminant, enters and is handled by the body following dermal exposure. A shallow glass cap covering approximately a 13-cm2 area was fixed tightly to the shaved skin of each adult male rat tested; 300 microL of 14C-benzene alone or with 1 g of clay or sandy soil was introduced under the cap through an opening which was sealed immediately. Pure benzene produced the highest peak plasma concentration of radioactivity, followed closely by sandy soil-adsorbed benzene, with the lowest value exhibited by clay soil-adsorbed benzene. The plasma elimination half-lives were as follows:sandy (24.5 hr), pure (23.0 hr), and clay (19.4 hr). The tissue concentrations of radioactivity 48 hr post administration were highest in treated skin (covered by the glass cap), followed by the kidney and liver in both soil-treated groups, and were highest in the kidney followed by the liver and treated skin in the pure group.(ABSTRACT TRUNCATED AT 250 WORDS)

Subchronic dermal toxicity studies of Alcide Allay gel and liquid in rabbits.

Alcide is a germicidal agent which is highly effective in killing a wide range of bacteria and fungi. 2.0 g kg-1 Allay gel or placebo were applied once per day while 3.0 g kg-1 Allay liquid or placebo were administered three times per day over a 30 day period to the skin of albino rabbits. Allay gel and liquid contained either of two concentrations of sodium chlorite and lactic acid as active ingredients. The concentration of active ingredients, sodium chlorite and lactic acid, in the low dose gel was 25% of high dose gel and low dose liquid was 60% of high dose liquid. Moderate to severe erythema was observed only in the high dose gel group after 7 days of treatment, but skin appeared visibly normal by day 18. Histologically fixed skin at day 30, however, showed inflammatory changes in the high and low dose gel groups and hyperkeratosis in all gel groups. At the termination of the study, mean corpuscular hemoglobin concentration decreased significantly in the Allay gel and liquid groups compared to an untreated control group. In all gel treatments, BUN/creatinine levels decreased significantly. Hematology and clinical chemistry parameters, however, were within the normal range of values for the gel and liquid groups, indicating no clinically significant changes due to Allay treatment. Pancreas/body weight ratios were significantly reduced in all gel groups, while spleen, pancreas and ovary/body weight ratios were significantly higher in both liquid dosage groups. No histological changes were observed in any of these organs.