Pharmacokinetics and bioavailability of diisopropanolamine (DIPA) in rats following intravenous or dermal application.

This study was conducted to determine the relative dermal bioavailability (absorption), distribution, metabolism, and excretion (ADME) of diisopropanolamine (DIPA), an alcohol amine used in a number of industrial and personal care products. Groups of 4 female Fischer 344 rats received either a single bolus i.v. dose of 19.0mg/kg (14)C-DIPA in water or a dermal application of 19.5mg/kg (14)C-DIPA in acetone to an area of 1cm(2) on the back and covered with a bandage. Time-course blood and excreta were collected and radioactivity determined. Urine was analyzed for DIPA and monoisopropanolamine (MIPA). Following i.v. administration, DIPA was rapidly cleared from the plasma and excreted into urine in a biexponential manner (t(1/2alpha), 0.4h; t(1/2beta), 2.9h). The levels of radioactivity in plasma dropped below the limit of detection 12h post-dosing. A total of 97+/-4% of the dose was actively excreted in urine by kidney, most ( approximately 71%) within 6h of dosing, virtually all as parent compound; renal clearance exceeded the glomerular filtration rate. Following dermal application, approximately 20% of the dose was absorbed in 48 h with the steady-state penetration rate of approximately 0.2%/h. Most (14.4%) of the applied radioactivity was excreted in urine at a relatively constant rate due to the presence of large amount of the (14)C-DIPA at the application site. Fecal elimination was <0.2% of the dose. The absorbed DIPA did not accumulate in tissues; only approximately 0.1% of the administered dose was found in liver and kidney. The absolute systemic dermal bioavailability (dose corrected AUC(dermal)/AUC(i.v.)) of (14)C-DIPA was 12%. The ADME of DIPA contrasts that of its diethanol analogue, diethanolamine, which displays a broad spectrum of toxicity in rats and mice. Toxicologically significant concentrations of DIPA are unlikely to be achieved in the systemic circulation and/or tissues as a result of repeated dermal application of products containing DIPA due to slow absorption from the skin, rapid unchanged elimination in urine, and majority of the products contain

Lack of differential sensitivity to cholinesterase inhibition in fetuses and neonates compared to dams treated perinatally with chlorpyrifos.

Pregnant Sprague-Dawley rats were exposed to chlorpyrifos (CPF; O,O-diethyl-O-[3,5,6-trichloro-2-pyridinyl] phosphorothioate) by gavage (in corn oil) from gestation day (GD) 6 to postnatal day (PND) 10. Dosages to the dams were 0 (control), 0.3 (low), 1.0 (middle) or 5.0 mg/kg/day (high). On GD 20 (4 h post gavage), the blood CPF concentration in fetuses was about one half the level found in their dams (high-dose fetuses 46 ng/g; high-dose dams 109 ng/g). CPF-oxon was detected only once; high-dose fetuses had a blood level of about 1 ng/g. Although no blood CPF could be detected (limit of quantitation 0.7 ng/g) in dams given 0.3 mg/kg/ day, these dams had significant inhibition of plasma and red blood cell (RBC) ChE. In contrast, fetuses of dams given 1 mg/kg/day had a blood CPF level of about 1.1 ng/g, but had no inhibition of ChE of any tissue. Thus, based on blood CPF levels, fetuses had less cholinesterase (ChE) inhibition than dams. Inhibition of ChE occurred at all dosage levels in dams, but only at the high-dose level in pups. At the high dosage, ChE inhibition was greater in dams than in pups, and the relative degree of inhibition was RBC approximately plasma > or = heart > brain (least inhibited). Milk CPF concentrations were up to 200 times those in blood, and pup exposure via milk from dams given 5 mg/kg/day was estimated to be 0.12 mg/kg/day. Therefore, the dosage to nursing pups was much reduced compared to the dams exposure. In spite of exposure via milk, the ChE levels of all tissues of high-dosage pups rapidly returned to near control levels by PND 5.

A Physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for the organophosphate insecticide chlorpyrifos in rats and humans.

A PBPK/PD model was developed for the organophosphate insecticide chlorpyrifos (CPF) (O,O-diethyl-O-[3,5,6-trichloro-2-pyridyl]-phosphorothioate), and the major metabolites CPF-oxon and 3,5,6-trichloro-2-pyridinol (TCP) in rats and humans. This model integrates target tissue dosimetry and dynamic response (i.e., esterase inhibition) describing uptake, metabolism, and disposition of CPF, CPF-oxon, and TCP and the associated cholinesterase (ChE) inhibition kinetics in blood and tissues following acute and chronic oral and dermal exposure. To facilitate model development, single oral-dose pharmacokinetic studies were conducted in rats (0.5-100 mg/kg) and humans (0.5-2 mg/kg), and the kinetics of CPF, CPF-oxon, and TCP were determined, as well as the extent of blood (plasma/RBC) and brain (rats only) ChE inhibition. In blood, the concentration of analytes followed the order TCP >> CPF >> CPF-oxon; in humans CPF-oxon was not quantifiable. Simulations were compared against experimental data and previously published studies in rats and humans. The model was utilized to quantitatively compare dosimetry and dynamic response between rats and humans over a range of CPF doses. The time course of CPF and TCP in both species was linear over the dose range evaluated, and the model reasonably simulated the dose-dependent inhibition of plasma ChE, RBC acetylcholinesterase (AChE), and brain (rat only) AChE. Model simulations suggest that rats exhibit greater metabolism of CPF to CPF-oxon than humans do, and that the depletion of nontarget B-esterase is associated with a nonlinear, dose-dependent increase in CPF-oxon blood and brain concentration. This CPF PBPK/PD model quantitatively estimates target tissue dosimetry and AChE inhibition and is a strong framework for further organophosphate (OP) model development and for refining a biologically based risk assessment for exposure to CPF under a variety of scenarios.

Determination of chlorpyrifos, chlorpyrifos oxon, and 3,5,6-trichloro-2-pyridinol in rat and human blood.

Analytical methods to quantitate chlorpyrifos and two potential metabolites, chlorpyrifos oxon (oxon) and 3,5,6-trichloro-2-pyridinol (TCP), in human and rat blood are described. Chlorpyrifos and the oxon were extracted simultaneously with a methanol/hexane mixture from 0.5 mL blood that was deactivated with an acidic salt solution. The extract was then concentrated and analyzed by negative-ion chemical ionization gas chromatography-mass spectrometry (NCI-GC-MS). TCP was extracted from a separate 0.1-mL aliquot of blood, also deactivated by the addition of acid. The t-butyldimethylsilyl derivative of TCP was formed using MTBSTFA, and the analysis was performed by NCI-GC-MS. Stable isotope analogues of chlorpyrifos (-13C2-15N), oxon (-13C2-15N), and TCP (-13C2) were used as internal standards. Oxon was observed to partially degrade to TCP during the sample analysis. Accurate oxon and TCP measurements were obtained with the use of oxon-13C2-15N, TCP-13C2, and TCP-13C2-15N internal standards, which compensated for both the degradation of oxon and the formation of artifactual TCP during analysis. The limits of quantitation were 1 ng/mL blood for both chlorpyrifos and oxon and 10 ng/mL for TCP. Calibration curves were linear over the concentration range of 2.5-2500 ng/mL solvent for chlorpyrifos and oxon and between 5 and 1060 ng/mL solvent for TCP. Taking concentration factors and extraction efficiencies into account, these linear ranges represent blood concentrations of approximately 0.3-300 ng/mL blood for chlorpyrifos and the oxon and 6-1300 ng/mL blood for TCP. The lowest spike level for chlorpyrifos and the oxon was 1 ng/mL blood, and the lowest spike level for TCP was 10 ng/mL blood. Recoveries from rat blood were as follows: 106-119% for chlorpyrifos, 94-104% for oxon, and 85-102% for TCP. In addition, chlorpyrifos and oxon were incubated with rat and human blood for various time intervals before deactivation to determine precautions that needed to be taken when collecting and handling specimens. No change in chlorpyrifos concentration was observed in rat blood up to 180 min at 37 degrees C. In contrast, the oxon was rapidly hydrolyzed to TCP in both rat (t 1/2 approximately 10 s) and human (t 1/2 approximately 55 s) blood held at 37 degrees C. The hydrolysis rate for the oxon was independent of whether a rat had been administered chlorpyrifos previously, the initial oxon concentration, the presence of chlorpyrifos, and the age or gender of the human volunteers. These results suggest rapid sample preparation is critical for accurate determinations of the oxon metabolite of chlorpyrifos. These methods provide excellent tools for use in chlorpyrifos pharmacokinetic modeling studies.

Children with special health-care needs in Texas.

A comprehensive system for the delivery of care to children with special healthcare needs and to their families has been developed by the department of pediatrics of The University of Texas Health Science Center at San Antonio. A description of the structure and operations of this system is presented and offered as a model for the state of Texas.

Childhood tuberculosis in North Carolina: a study of the opportunities for intervention in the transmission of tuberculosis to children.

New cases of tuberculosis in children continue to appear. A retrospective review of the medical records of a representative sample of such cases occurring from 1977 through 1981 was conducted to gain an understanding of why this preventable disease continues to occur in North Carolina children. Three per cent of cases were detected by routine screening; 17 per cent were diagnosed after the child's symptomatic presentation; and 80 per cent after contact screening. However, 14 per cent of cases detected by contact screening developed disease while receiving isoniazid prophylaxis for a positive tuberculin test; and 19 per cent of cases detected by contact screening developed disease while under surveillance, but not receiving isoniazid prophylaxis, as tuberculin negative contacts of known infectious cases. Adherence to accepted recommendations for prophylaxis should reduce the childhood tuberculosis case rate.

Quantitative measurement of water consumption patterns in lactating female and neonatal Fischer 344 rats employing [14C]methylcellulose.

Lactating female and neonatal Fischer 344 rats were given water containing [14C]methylcellulose, a nonabsorbed marker, over a 24-hr interval on Days 13, 15, 18, 21, 24, and 27 postpartum. The amount of water consumed was calculated based on the 14C activity recovered in the feces and gastrointestinal tract. Maternal water consumption during the first 28 days postpartum, when expressed as g/kg/day, averaged 2.5 times the level consumed by nonlactating female rats. Maternal water consumption peaked on Day 21 postpartum at 3.3 times the level measured in nonlactating female rats of comparable age. Neonatal water consumption began on Day 18 postpartum and by Day 28 postpartum was 1.9 times the level observed in nonlactating females. Average neonatal water consumption between Days 21 and 28 postpartum was 1.3 times the level for nonlactating female rats. These data indicate that when the test material is administered via the drinking water the dose levels received by the maternal and neonatal rats have been routinely underestimated, and that conclusions concerning the dose-response relationship or increased sensitivity during this period must be tempered by these results.

Pharmacokinetics of triclopyr (3,5,6-trichloro-2-pyridinyloxyacetic acid) in the beagle dog and rhesus monkey: perspective on the reduced capacity of dogs to excrete this organic acid relative to the rat, monkey, and human.

The pharmacokinetics of triclopyr (3,5,6-trichloro-2-pyridinyloxyacetic acid) were measured in the beagle dog and rhesus monkey and compared with the kinetics observed in rats and humans. In addition, studies were conducted in anesthetized dogs to better understand the mechanism by which [14C]triclopyr is eliminated in this species. Triclopyr was dissolved in distilled water, and administered as a single oral dose of 0.5, 5, or 20 mg/kg to three male dogs. A single male rhesus monkey was given an intravenous dose of 30 mg [14C]triclopyr/kg body wt on two occasions separated by 10 days. Anesthetized male dogs, were implanted with venous, arterial, and urethral catheters and given increasing amounts of triclopyr to produce plasma triclopyr levels ranging from 0.3 to 27 microg eq/mL. In the monkey, triclopyr was rapidly eliminated from the plasma (t1/2 = 6.3 hr) with >95% of the urinary 14C activity excreted within 24 hr postdosing. In the dog, orally administered triclopyr was rapidly and effectively absorbed at every dose level with virtually all of it excreted in the urine by 72 hr postdosing. However, the kinetics were slightly nonlinear, and the fraction of the dose excreted in the urine decreased with increasing dose. Several nonlinear processes may collectively contribute to the modest nonlinear pharmacokinetics in the dog. Plasma protein binding of triclopyr in the dog ranged from 94 to 99%, was nonlinear, and was an important determinant in the renal clearance of triclopyr. The nonlinear plasma protein binding indicates that glomerular filtration became disproportionately more important as plasma triclopyr concentration increased. There was good evidence for a high-affinity low-capacity active-secretory process that was saturated by low plasma triclopyr concentrations. As plasma triclopyr concentrations increased, tubular reabsorption begins to exceed secretion, resulting in decreased renal clearance. The volume of distribution, normalized for body weight, was constant across all species. While clearance and half-life could be allometrically scaled to body weight for the rat, monkey, and human, the dog had a much slower clearance and longer half-life for triclopyr elimination than predicted allometrically. These data demonstrate that the pharmacokinetics of triclopyr in the dog are markedly different than in rat, monkey, and human.

Nonlinear kinetics of inhaled propylene glycol monomethyl ether in Fischer 344 rats following single and repeated exposures.

The kinetics of propylene glycol monomethyl ether (PGME) and its demethylated metabolite, propylene glycol (PGLY), were investigated with the aim of describing concentration- and treatment-related changes in absorption and clearance. Groups of Fischer 344 rats received either 1 or 10 daily 6-hr inhalation exposures to PGME. Single exposures were performed using both nose-only (300, 750, 1500, and 3000 ppm) and whole-body (300 and 3000 ppm) inhalation techniques, whereas multiple exposures (300 and 3000 ppm) were confined to the whole-body procedure. PGME blood levels failed to plateau during a 6-hr inhalation exposure, indicating that absorption was limited by respiration. The clearance of PGME from the blood could be described as a pseudo-zero-order process following each exposure concentration and treatment regimen examined. PGLY blood levels indicated that the demethylation of PGME to PGLY was saturated at exposure concentrations exceeding 1500 ppm. PGME blood levels were higher in male than in female rats receiving a single 3000 ppm exposure. Unlike the results from a single exposure, PGME elimination was essentially complete 24 hr after the last of 10 consecutive 3000 ppm exposures. The changes in PGME elimination following multiple 3000 ppm exposures were associated with higher in vitro levels of cytochrome P-450 and mixed-function oxidase activity. Multiple exposures to 300 ppm did not affect PGME elimination or in vitro microsomal metabolism.

Determination of styrene-7,8-oxide in whole rat blood by gas chromatography-mass spectrometry.

A rapid and selective method for the determination of styrene-7,8-oxide (SO) in whole blood has been developed. Blood samples as small as 0.1 ml are extracted once with benzene containing phenyl propylene oxide as an internal standard. The extracts are analyzed by gas chromatography-mass spectrometry using an automated cold on-column injection system to avoid thermal rearrangement of SO to phenylacetaldehyde. The overall mean recovery (+/- 2 sigma) of SO from fortified blood samples was 92 +/- 21% and the detection limit was 10 ng/g. Results of experiments examining the half-life of SO in whole rat blood are presented. The method was also used to analyze sequential blood samples from rats administered SO orally.

Cerebral and blood glucose in central oxygen poisoning.

Studies were carried out to determine the effect of high oxygen pressure (OHP) on brain and blood glucose. OHP increased cerebral glucose in mice killed at various stages of oxygen toxicity. This included times which corresponded to 75% and 100% of the CT50, the hyperactive state, and at seizure onset. Blood glucose also was increased but only when mice were exposed to oxygen for times which produced stress-related responses. These were at 100% of the CT50,during hyperactivity, and at the onset of seizures. The increase in cerebral glucose was due to the increased oxygen pressure and not to the pressure per se. Adrenalectomy blocked the oxygen-induced increase in blood glucose but not in cerebral glucose. Disulfiram, an effective oxygen protectant, markedly increased both brain and blood glucose.

Oral and dermal pharmacokinetics of triclopyr in human volunteers.

Blood levels and urinary excretion of triclopyr, the active ingredient in Garlon herbicides, were followed in six volunteers given single oral doses of 0.1 and 0.5 mg/kg body weight. Five of these volunteers later received dermal applications of Garlon 4 herbicide formulation equivalent to 3.7 mg triclopyr/kg body weight applied to the forearm. Following oral administration blood levels peaked at 2-3 h and declined to undetectable levels within 48 h; more than 80% of the dose was found as unchanged triclopyr in the urine. A two-compartment pharmacokinetic model was used to describe the time-course of triclopyr clearance; half-lives for the rapid initial and slower terminal phases were 1.3 h and 5.1 h respectively, and were independent of dose. Due to the slow half-life for dermal absorption (t1/2 = 16.8 h) the rapid initial elimination phase was obscured and the pharmacokinetics could be simplified by a one-compartment model. An average of 1.37% of the applied dose was recovered in the urine; when corrected for recovery after oral administration this was equivalent to an absorption of 1.65%. Triclopyr is slowly absorbed through skin and is rapidly eliminated. It has very low potential to accumulate in man or to be absorbed through the skin in acutely toxic amounts.

Pharmacokinetics of picloram in male volunteers.

The fate of picloram (4-amino-3,5,6-trichloropicolinic acid), an active ingredient in TORDON brand herbicides, was defined in 6 healthy male volunteers following single po doses of 5.0 and 0.5 mg/kg, and a dermal dose of 2.0 mg/kg. Picloram was administered orally as the sodium salt in grape juice. The dermal dose was applied to the volunteers' backs as the free acid dissolved in ethanol. The data indicate picloram was rapidly absorbed from the gastrointestinal tract (t1/2 = 20 min) and rapidly excreted unchanged in the urine. Over 90% of the po dose was recovered as unchanged picloram in the urine excreted through 72 hr; most of the dose (greater than 75%) was excreted within 6 hr and the remainder was excreted with an average half-life of 27 hr. By comparison picloram was slowly absorbed through the skin (t1/2 = 12 hr) and, based on the quantity of picloram excreted in the urine, only a small fraction (0.2%) of the picloram applied to the skin was absorbed. These data indicate that picloram because of its rapid excretion has a low potential to accumulate in man during repeated or prolonged exposures. In addition, picloram was poorly absorbed through human skin and it is unlikely that acutely toxic quantities will be absorbed by this route.

Chlorpyrifos: pharmacokinetics in human volunteers.

The kinetics of chlorpyrifos, an organophosphorothioate insecticide, and its principal metabolite, 3,5,6-trichloro-2-pyridinol (3,5,6-TCP), were investigated in six healthy male volunteers given a single 0.5 mg/kg po and, 2 or more weeks later, a 0.5 or 5.0 mg/kg dermal dose of chlorpyrifos. No signs or symptoms of toxicity or changes in erythrocyte cholinesterase were observed. Plasma cholinesterase was depressed to 15% of predose levels by the 0.5 mg/kg po dose but was essentially unchanged following the 5.0 mg/kg dermal dose. Blood chlorpyrifos concentrations were extremely low (less than 30 ng/ml), and no unchanged chlorpyrifos was found in the urine following either route of administration. Mean blood 3,5,6-TCP concentrations peaked at 0.93 micrograms/ml 6 hr after ingestion of the oral dose and at 0.063 micrograms/ml 24 hr after the 5.0 mg/kg dermal dose. 3,5,6-TCP was cleared from the blood and eliminated in the urine with a half-life of 27 hr following both the po and dermal doses. An average of 70% of the po dose but less than 3% of the dermal dose was excreted in the urine as 3,5,6-TCP; thus only a small fraction of the dermally applied chlorpyrifos was absorbed. Chlorpyrifos and its principal metabolite were rapidly eliminated and therefore have a low potential to accumulate in man on repeated exposures. Based on these data, blood and/or urinary 3,5,6-TCP concentrations could be used to quantify the amount of chlorpyrifos absorbed under actual use conditions.

A physiologic pharmacokinetic model for styrene and styrene-7,8-oxide in mouse, rat and man.

Concern about the carcinogenic potential of styrene (ST) is due to its reactive metabolite, styrene-7,8-oxide (SO). To estimate the body burden of SO resulting from various scenarios, a physiologically based pharmacokinetic (PBPK) model for ST and its metabolite SO was developed. This PBPK model describes the distribution and metabolism of ST and SO in the rat, mouse and man following inhalation, intravenous (i.v.), oral (p.o.) and intraperitoneal (i.p.) administration of ST or i.v., p.o. and i.p. administration of SO. Its structure includes the oxidation of ST to SO, the intracellular first-pass hydrolysis of SO catalyzed by epoxide hydrolase and the conjugation of SO with glutathione. This conjugation is described by an ordered sequential ping-pong mechanism between glutathione, SO and glutathione S-transferase. The model was based on a PBPK model constructed previously to describe the pharmacokinetics of butadiene with its metabolite butadiene monoxide. The equations of the original model were revised to refer to the actual tissue concentration of chemicals instead of their air equivalents used originally. Blood:air and tissue:blood partition coefficients for ST and SO were determined experimentally and have been published previously. Metabolic parameters were taken from in vitro or in vivo measurements. The model was validated using various data sets of different laboratories describing pharmacokinetics of ST and SO in rodents and man. In addition, the influences of the biochemical parameters, alveolar ventilation and blood:air ventilation and blood:air partition coefficient for ST on the pharmacokinetics of ST and SO were investigated by sensitivity analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

A rapid and simple radioactive method for the determination of disulfiram and its metabolites from a single sample of biological fluid or tissue.

An analytical method is described for the determination of radioactive disulfiram, diethyldithiocarbamate, diethyldithiocarbamate-methyl ester, diethyldithiocarbamate-glucuronide, inorganic sulfate, and a protein bound S35 fraction from a single sample of either plasma, urine or tissue. The procedure is based upon quantitative stepwise extraction or precipitation of the individual compounds, and is both specific and precise. The applicability of the methods developed for the determination of S35 disulfiram and its S35 metabolites in plasma and urine from a dog given S35 disulfiram i.v., and in mouse brain from mice given S35 disulfiram i.p. are illustrated.

Human red blood cell acetylcholinesterase inhibition as the appropriate and conservative surrogate endpoint for establishing chlorpyrifos reference dose.

Chlorpyrifos (O,O-diethyl O-(3,5, 6-trichloro-2-pyridinyl)- phosphorothioate) is an organophosphorus (OP) insecticide used for controlling insect pests. Currently, the reference dose (RfD) used by the Environmental Protection Agency (EPA) to establish acceptable human exposure tolerances for chlorpyrifos is based upon inhibition of blood butyrylcholinesterase (BuChE), which is not the target enzyme of chlorpyrifos, and does not play any role in cholinergic transmission. Data are presented showing that inhibition of acetylcholinesterase (AChE) associated with red blood cells (RBC), an enzyme similar to or identical with that in the nervous system, is a more appropriate endpoint on which to base the RfD. Basing an acceptable level of human exposure (e.g., RfD) on inhibition of RBC AChE provides a significant margin of safety, since it is 12- to 14-fold more sensitive as an indicator of chlorpyrifos exposure than the AChE in the most sensitive relevant neurological tissues (brain or retina). Inhibition of RBC AChE activity is consistently exhibited at lower dosages of chlorpyrifos than those required to result in clinical symptoms of OP toxicity, or alterations in cognitive functional responses. There is no unique sensitivity of the fetus or neonates to chlorpyrifos when administered by an appropriate oral dose. Thus, inhibition of RBC AChE activity is an appropriate surrogate measurement of chlorpyrifos exposure and provides a conservative endpoint for establishing appropriate margins of safety for both adults and infants.

Acute, pharmacokinetic, and subchronic toxicological studies of 2,4-dichlorophenoxyacetic acid.

The single-dose oral LD50 values in Fischer 344 rats for technical-grade, 2,4-dichlorophenoxyacetic acid (2,4-D), esters, and salts ranged from 553 mg/kg (isobutyl ester in females) to 1090 mg/kg (dimethylamine salt in males). The LD50 values for the acid, esters, or salts, when expressed as acid equivalents, were consistent which suggests that the acute toxicity was due to 2,4-D per se. Acute dermal LD50 values in rabbits for the acid, esters, and salts were greater than 2000 mg/kg. Overall, these results indicate that the acute oral and dermal toxicity of 2,4-D are low. Pharmacokinetics were evaluated in male Fischer 344 rats given single oral doses of 10, 25, 50, 100, or 150 mg 2,4-[14C]D/kg. The amount of 2,4-D in the plasma, kidney, and urine 6 hr postdosing indicated that the urinary elimination of 2,4-D was saturated in male rats given oral doses in excess of 50 mg/kg. Subchronic dietary studies in male and female Fischer 344 rats used dose levels of 0, 15, 60, 100, or 150 mg/kg/day of purified or technical-grade 2,4-D acid for 13 weeks. Body weight gains were decreased for both sexes at the higher dose levels of purified and technical-grade 2,4-D acid. Kidney weights were increased in all treated male rats and in females given the higher three dose levels of purified 2,4-D. Treatment-related cytoplasmic alterations were present in the renal proximal tubules of most rats given 60 mg/kg/day and higher of purified or technical-grade 2,4-D; a few females given 15 mg/kg/day also had slight alterations in the cytoplasm of the proximal tubules. A dose-related degenerative change was identified in the descending proximal renal tubules of all male rats given the highest three dose levels of either test material and some given 15 mg/kg/day. Dose levels of 100 or 150 mg/kg/day of either compound for both sexes produced minimal swelling and increased staining homogeneity in the liver cells and were associated with a slight elevation of liver weight and serum glutamic pyruvic transaminase activity. Higher dose levels of technical-grade and purified 2,4-D decreased total serum tetraiodothyronine levels in female rats, however, the morphology of the thyroid gland was normal. The no-observed-effect level (NOEL) was less than 15 mg/kg/day for both purified and technical-grade 2,4-D acid.

Physiologically based pharmacokinetic modeling with methylchloroform: implications for interspecies, high dose/low dose, and dose route extrapolations.

A unified physiologically based pharmacokinetic (PB-PK) model was developed and used to describe the disposition of methylchloroform (1,1,1-trichloroethane, MC) in three different species (rats, mice, and humans) after four different routes of exposure (inhalation, intravenous injection, bolus gavage, and drinking water administration). Metabolism of MC followed Michaelis-Menten kinetics in each species. Vmax's were calculated from the allometric equation: Vmax = 0.419 BW0.7, and Km appeared to be identical in each species (5.75 mg equivalents/liter). Once the PB-PK model had been developed for young adult animals (1-3 months of age), it was used to study the disposition of MC in older rats and mice (approximately 18.5 months of age). Most of the changes in the pharmacokinetic behavior of MC in older rats could be simulated by increasing the size of the fat compartment in the PB-PK model from 7 to 18% of body weight. However, the pharmacokinetic behavior in older mice was more complex; increasing the size of the fat compartment in this species from 4 to 18% only accounted for part of the observed differences between old and young animals. An appropriate dose surrogate (average area under the liver concentration/time curve) was selected and the PB-PK model was used to make quantitative comparisons between "internal doses" of MC in long term animal studies and "internal doses" associated with human exposures to MC. Values of the dose surrogate in humans consuming 2 liters/day of water with typical levels of MC contamination (1-10 ppb) were four to six orders of magnitude lower than the dose surrogates in the rodent studies at levels of MC exposure which failed to produce adverse effects on the liver (875-1500 ppm, 6 hr/day, 5 days/week).

Kinetics and metabolism of inhaled methyl chloroform (1,1,1-trichloroethane) in male volunteers.

The kinetics of inhaled methyl chloroform (MC) and its principal metabolites, trichloroethanol (TCE) and trichloroacetic acid (TCA), were defined in six healthy male volunteers following single 6-hr exposures of 350 and 35 ppm. Blood and expired air MC concentrations were proportional to the exposure concentration and indicated that about 25% of the MC inhaled during the 6-hr exposure was absorbed. Elimination of MC was triexponential with half-lives estimated as 44 min, 5.7 hr, and 53 hr for the initial, intermediate, and terminal phases. Over 91% of the absorbed MC was excreted unchanged via the lungs, 5-6% was metabolized and excreted as TCE and TCA, and less than 1% remained in the body after 9 days. Urinary TCE and TCA excretion was extremely variable and indicated that urinary TCE and TCA measurements provide at best only a rough estimate of the exposure. These data suggest that the kinetics of MC in man are essentially first order at or below the current TLV of 350 ppm. Based on a comparison of the blood MC levels and amounts of MC metabolized, the rat is a better model than the mouse to predict the toxicity of MC in man.