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Biomedical subjects

R A Howd

Publications and source records attributed to R A Howd.

At least 19 recordsLinked to original sources
PubMed1994

Dose-response assessment of airborne methyl isothiocyanate (MITC) following a metam sodium spill.

A tank car derailment in northern California in 1991 spilled metam sodium into the Sacramento River, and released its breakdown product, methyl isothiocyanate (MITC), into the air. This paper describes the risk evaluation process used. Over 240 individuals reported symptoms such as eye and throat irritation, dizziness, and shortness of breath. Reference exposure levels (RELs) for 1 hr were developed for MITC and compared to exposure concentrations. Ocular irritation in cats was the most sensitive endpoint reported. The no observed adverse effect level (NOAEL), divided by an uncertainty factor (UF) of 100, produced an REL of 0.5 ppb of MITC in air to prevent discomfort. An REL to prevent disability was estimated to be 40 ppb. An REL to prevent life-threatening injury was estimated to be 150 ppb. Measured MITC levels ranged from 0.2-37 ppb and estimated peak levels ranged from 140-1600 ppb. The usefulness of RELs for emergency planning is discussed.

Accidents↗
PubMed1992

Estimating dermal uptake of nonionic organic chemicals from water and soil: I. Unified fugacity-based models for risk assessments.

Contamination of water and soil that might eventually contact human skin makes it imperative to include the dermal uptake route in efforts to assess potential environmental health risks. Direct measurements of dermal uptake from either water or soil are only available for a small number of the thousands of chemicals likely to be found in the environment. We propose here a mass-transfer model for estimating skin permeability and dermal uptake for organic chemicals that contaminate soil and water. Statistical relationships between measured permeabilities and chemical properties reveal that permeability varies primarily with the octanol-water partition coefficient (Kow) and secondarily with the molecular weight. From these results, we derive a fugacity-based model for skin permeability that addresses the inherent permeability of the skin, the interaction of the skin with the environmental medium on skin (water or soil), and retains a relatively simple algebraic form. Model predictions are compared to measured human skin permeabilities for some 50 compounds in water and four compounds in soil. The model is adjusted to account for dermal uptake during both short-term (10-20 min) and long-term (several hour) exposures. This model is recommended for compounds with molecular weight less than or equal to 280 g.

Biological Transport, Active↗
PubMed1989

Quaternary salts of 2-[(hydroxyimino)methyl]imidazole. 2. Preparation and in vitro and in vivo evaluation of 1-(alkoxymethyl)-2-[(hydroxyimino)methyl]-3-methylimida zolium halides for reactivation of organophosphorus-inhibited acetylcholinesterases.

A series of structurally related mono- and bis-1,3-disubstituted 2-[(hydroxyimino)methyl]imidazolium halides were evaluated in vitro for their ability to reactivate electric eel, bovine, and human erythrocyte (RBC) acetylcholinesterases (AChE) inhibited by ethyl p-nitrophenyl methylphosphonate (EPMP) and 3,3-dimethyl-2-butyl methyl-phosphonofluoridate (soman, GD). All new compounds were characterized for (hydroxyimino)methyl acid dissociation constant, nucleophilicity, octanol-buffer partition coefficient, reversible AChE inhibition, and kinetics of reactivation of EPMP-inhibited AChEs. For GD-inhibited AChEs, maximal reactivation was used to compare compounds since rapid phosphonyl enzyme dealkylation "aging" complicated interpretation of kinetic constants. For comparison, we also evaluated three known pyridinium therapeutics, 2-PAM, HI-6, and toxogonin. In vivo evaluation in mice revealed that when selected imidazolium compounds were coadministered with atropine sulfate, they were effective in providing lifesaving protection against both GD and EPMP challenges. This was a major accomplishment in the search for effective anticholinesterase therapeutics--the synthesis and preliminary evaluation of the first new monoquaternary soman antidotes with potencies superior to 2-PAM. Significantly, there was an apparent inverse relationship between in vitro and in vivo results; the most potent in vivo compounds proved to be the poorest in vitro reactivators. These results suggested that an alternative and possibly novel antidotal mechanism of protective action may be applicable for the imidazolium aldoximes. Selected compounds were also evaluated for their inhibition of AChE phosphorylation by GD and antimuscarinic and antinicotinic receptor blocking effects.

Animals↗
PubMed1989

Quaternary salts of 2-[(hydroxyimino)methyl]imidazole. 3. Synthesis and evaluation of (alkenyloxy)-, (alkynyloxy)-, and (aralkyloxy)methyl quaternarized 2-[(hydroxyimino)methyl]-1-alkylimidazolium halides as reactivators and therapy for soman intoxication.

A series of structurally related monosubstituted 1-[(alkenyloxy)methyl]-, 1-[(alkynyloxy)methyl]-, and 1-[(aralkyloxy)methyl]-2-[(hydroxyimino)methyl]-3-methyli midazolium halides were prepared and evaluated. All new compounds were characterized with respect to (hydroxyimino)methyl acid dissociation constant, nucleophilicity, and octanol-buffer partition coefficient. The alkynyloxy-substituted compounds were also evaluated in vitro with respect to reversible inhibition of human erythrocyte (RBC) acetylcholinesterase (AChE) and kinetics of reactivation of human AChE inhibited by ethyl p-nitrophenyl methylphosphonate (EPMP). In vivo evaluation in mice revealed that coadministration of alkynyloxy-substituted imidazolium compounds with atropine sulfate provided significant protection against a 2 x LD50 challenge of GD. For the alkynyloxy-substituted imidazolium drugs there is a direct relationship between in vitro and in vivo activity: the most potent in vivo compounds against GD proved to be potent in vitro reactivators against EPMP-inhibited human AChE. These results differ from the observations made on the sterically hindered imidazolium compounds (see previous article) and suggest that several antidotal mechanisms of protective action may be applicable for the imidazolium aldoxime family of therapeutics. The ability of the alkynyloxy substituents to provide life-saving protection against GD intoxication was not transferable to the pyridinium or triazolium heteroaromatic ring systems.

Animals↗
PubMed1987

Hearing loss in rats caused by inhalation of mixed xylenes and styrene.

We have reported that inhalation exposure of rats to toluene causes permanent hearing loss, e.g. Pryor et al. Neurobehav. Toxicol. Teratol. 5, 53-62 (1983). Therefore, it was of considerable interest to examine the ototoxic potential of two structurally related solvents--mixed xylenes and styrene--compared with that of toluene. Male, weanling Fischer-344 rats were exposed to clean air or solvents in four identical 62.5 l Plexiglas chambers. Exposures to 800, 1000, and 1200 ppm were daily for 14 hours/day and lasted 6 weeks for mixed xylenes, 3 weeks for styrene. An additional experiment with xylenes examined the effect of exposure for only 4 (1700 ppm) or 8 (1450 ppm) hours or for 8 (1450 ppm) hours on three consecutive days to compare the results with those obtained with toluene under comparable exposure schedules. Both xylenes and styrene caused marked hearing loss as assessed by behavioral (conditioned avoidance) and electrophysiologic (brainstem auditory-evoked response) methods. Moreover, both solvents appeared to be more potent ototoxicants than toluene, as indicated by effective concentration, effective durations of exposure, and the range of frequencies affected.

Animals↗
PubMed1986

Nonquaternary cholinesterase reactivators. 4. Dialkylaminoalkyl thioesters of alpha-keto thiohydroximic acids as reactivators of ethyl methylphosphonyl- and 1,2,2-trimethylpropyl methylphosphonyl-acetylcholinesterase in vitro.

In the search for improved lipophilic centrally active acetylcholinesterase (AChE) antidotes, a series of alpha-keto thiohydroximates were prepared and evaluated for their ability to reactivate AChEs inhibited by ethyl p-nitrophenyl methylphosphonate (EPMP) and soman (GD). The compounds conformed to the general structure 4-RC6H5C-(O)C(NOH)S(CH2)nN+R'R''.X- where R = H, CH3, F, Br, Cl, OCH3, CN;R' = CH3, C2H5, i-C3H7; R'' = H, CH3; X = Cl, I; and n = 2, 3. In this series, varying R substituents on the aryl ring produced compounds with oxime pKa values from 6.8 to 8.0, optimum for an AChE reactivator. Increasing lipophilicity of the amine segment correlated with reactivator potency, as did electron-withdrawing groups on the aryl moiety, presumably due to increased binding to hydrophobic sites surrounding the AChE active site. The in vitro reactivation potency of the alpha-keto thiohydroximates approaches and even surpasses that of 2-PAM and toxogonin for GD-inhibited AChE. These initial findings point to additional structure-activity relationships to assist in the design of improved antidotal compounds.

Acetylcholinesterase↗
PubMed1986

Nonquaternary cholinesterase reactivators. 3. 3(5)-Substituted 1,2,4-oxadiazol-5(3)-aldoximes and 1,2,4-oxadiazole-5(3)-thiocarbohydroximates as reactivators of organophosphonate-inhibited eel and human acetylcholinesterase in vitro.

As an extension of an earlier investigation (J. Med. Chem. 1984, 27, 1431), we prepared a series of 3-substituted 5-[(hydroxyimino)methyl]-1,2,4-oxadiazoles and the corresponding 5-thiocarbohydroximic acid 2-(N,N-dialkylamino)ethyl S-esters. The compounds were evaluated in vitro as reactivators of phosphonylated electric eel and human erythrocyte (RBC) acetylcholinesterases (AChE). The compounds were characterized with respect to (hydroxyimino)methyl acid dissociation constant, nucleophilicity, octanol/buffer partition coefficient, reversible AChE inhibition, and kinetics of reactivating ethyl methylphosphonylated AChE. One compound was also tested for effectiveness in preventing AChE phosphonylation. All of the tested compounds significantly reactivate ethyl methylphosphonylated AChE: the 3-n-octyl- and 3-(1-naphthyl)-substituted aldoximes are as reactive (within a factor of 5-10) toward the inhibited enzymes as the benchmark pyridinium reactivators, 2-PAM and HI-6. All of the substituted thiocarbohydroximic acid S-esters are powerful reversible inhibitors of AChE's: the 3-n-octyl- and 3-(1-naphthyl)-substituted thiocarbohydroximates inhibit eel AChE to 50% initial activity at concentrations less than 5 microM. When added to an eel AChE solution at concentrations between 5 and 50 microM, the 3-phenyl-substituted thiocarbohydroximate effectively antagonizes AChE inhibition by ethyl p-nitrophenyl methylphosphonate (EPMP), suggesting the potential utility of this compound for preventing anti-AChE-agent poisoning.

Acetylcholinesterase↗
PubMed1985

Interactions between toluene and alcohol.

Weanling male Fischer-344 rats were exposed by inhalation to air or 2000 ppm toluene for 8 hours each day for 2 weeks. Subgroups had access to water or 6% alcohol as their only fluid sources, respectively. Rats exposed to both toluene and alcohol subsequently showed a marked preference for 6% alcohol in two-bottle choice tests that persisted for up to 20 days for some rats. Rats exposed to toluene without access to alcohol and control rats (exposed to air and water) showed a marked aversion to the alcohol solution, and only 2 of 12 rats forced to drink alcohol without exposure to toluene preferred alcohol in the preference tests. Exposure to both toluene and alcohol also caused greater inhibition of weight gain than exposure to either substance alone, accompanied by greater signs of organ toxicity as indicated by clinical blood chemistries. Exposure to toluene caused marked hearing loss as assessed by a behavioral technique (conditioned avoidance), and there was a trend toward enhancement of this ototoxic effect by forced consumption of alcohol.

Alcohol Drinking↗
PubMed1984

Nonquaternary cholinesterase reactivators. 2. Alpha-heteroaromatic aldoximes and thiohydroximates as reactivators of ethyl methylphosphonyl-acetylcholinesterase in vitro.

We prepared six pairs of alpha-heteroaromatic aldoximes, RC(= NOH)H, and thiohydroximates, RC(= NOH)S-(CH2)2N(C2H5)2, where R represents various oxadiazole and thiadiazole rings. Each compound was characterized with respect to the following: structure, (hydroxyimino)methyl acid dissociation constant, nucleophilicity toward trigonal carbon and tetrahedral phosphorus, octanol-buffer partition coefficient, reversible inhibition of eel acetylcholinesterase (AChE), and in vitro reactivation of AChE inhibited by ethyl p-nitrophenyl methylphosphonate. Eight of the twelve compounds significantly reactivate ethyl methylphosphonyl-AChE, but inherent reactivities are moderate to low: the most potent nonquaternary reactivator, 3-phenyl-5-[(hydroxyimino)methyl]-1,2,4-oxadiazole, is 17 times less reactive than the well-known reactivator 2-[(hydroxyimino)methyl]-1-methylpyridinium iodide (2-PAM). One of the nonquaternary compounds, 3-phenyl-1,2,4-oxadiazole-5-thiohydroximic acid 2-(diethylamino)ethyl S-ester, is a powerful reversible inhibitor of AChE (I50 = 7.5 microM). The observed relationships between nonquaternary compound structure, reactivation potency, and anti-AChE activity reveal important molecular requirements for high reactivity toward phosphonylated AChE.

Binding Sites↗
PubMed1984

Structure-activity relationships for reactivators of organophosphorus-inhibited acetylcholinesterase: quaternary salts of 2-[(hydroxyimino)methyl]imidazole.

A series of 1,3-disubstituted-2-[(hydroxyimino)methyl]imidazolium halides were prepared and evaluated in vitro with respect to their ability to reactivate acetylcholinesterase inhibited by ethyl p-nitrophenyl methylphosphonate (EPMP) and 3,3-dimethyl-2-butyl methylphosphonofluoridate (GD). The compounds conform to the general formula N(CH3)C(CHNOH)N(CH2OR)CHCH+ X Cl-, where R = CH3, (CH2)3CH3, (CH2)7CH3, CH2C6H5, CH2C10H7, (CH2)3C6H5, CH(CH3)2, CH2C(CH3)3, and CH(CH3)C(CH3)3. For comparison we also evaluated three known pyridinium reactivators, 2-PAM, HI-6, and toxogonin. The imidazolium aldoximes exhibit oxime acid dissociation constants (pKa) in the range 7.9-8.1, bracketing the value of 8.0, believed to be optimal for acetylcholinesterase reactivation. With imidazolium compound in excess over inhibited enzyme, the kinetics of reactivation are well behaved for EPMP-inhibited AChE and depend on the nature of the alkyl ether group R. For GD-inhibited AChE, maximal reactivation was used to compare compounds because rapid phosphonyl enzyme dealkylation and enzyme reinhibition complicate interpretation of kinetic constants.

Acetylcholinesterase↗
PubMed1982

Oral ethanol intake nad levels of blood alcohol in the squirrel monkey.

Oral alcohol ingestion and blood alcohol levels were examined in adult female squirrel monkeys to assess the feasibility of using this primate as a model for fetal alcohol effects. In one experiment, alcohol intake was evaluated in nonpregnant animals under conditions in which the concentration of ethanol, length of ethanol exposure, and degree of liquid deprivation were varied. In another experiment blood alcohol levels were measured in pregnant animals of two subtypes that had been drinking ethanol. In a third experiment, time-dependent blood alcohol levels and behavior were evaluated in nonpregnant monkeys following intubation of specific doses of ethanol. Results showed that nonpregnant monkeys drank ethanol at concentrations of 5 to 10%, and that the amount of ethanol consumed was related to the concentration and length of time ethanol was available. When given access to a 5% ethanol solution, pregnant animals drank quantities that varied between individuals and subtypes, with maximum blood levels, measured up to 6 hr after presentation, ranging from 1 to 196 mg%. Intubation of ethanol resulted in blood alcohol levels and incoordination scores that were linearly related to dose, with maximum effects occurring 1 hr after administration. Elimination of ethanol from the blood at levels above 50 mg% occurred at a rate of about 35 mg%/hr, while the rate of clearance from the body was calculated to be approximately 250 mg/kg/hr.

Alcohol Drinking↗
PubMed1982

Effects of PAM, proPAM, and DFP on behavior, thermoregulation, and brain AChE in rats.

The effects of pyridine-2 aldoxime methyl iodide (PAM), N-methyl-1,6-dihydro-pyridine-2-carbaldoxime hydrochloride (proPAM), and diisopropyl phosphorofluoridate (DFP) on performance of a conditioned avoidance response (CAR), body temperature, and in vivo acetylcholinesterase (AChE) activity in five brain regions in the rat were examined. Sublethal doses of DFP (1.5 to 2.5 mg/kg, IP) markedly degraded CAR performance. This effect was antagonized by 5 mg/kg, subcutaneously injected (SC) atropine. A 50 mg/kg, SC dose of PAM had no effect on the CAR, but an equal dose of proPAM caused a transient deterioration of performance. Given 10 min or 2 hr after DFP, 50 mg/kg proPAM initially exacerbated the behaviorally toxic effects of DFP. Neither PAM nor proPAM antagonized DFP-induced hypothermia. PAM did not reactivate DFP-inhibited brain AChE, and proPAM reactivated it by only 6 to 12% of control activity.

Acetylcholinesterase↗
PubMed1981

Nonquaternary cholinesterase reactivators. Dialkylaminoalkyl thioesters of alpha-ketothiohydroximic acids as reactivators of diisopropyl phosphorofluoridate inhibited acetylcholinesterase.

We have prepared a series of alpha-ketothiohydroximic acid thioesters and evaluated them in vitro with respect to their ability to reactivate (diisopropylphosphoryl)acetylcholinesterase. The compounds conform to the general formula RC(=O)C(=NOH)S(CH2)nNR2'.HCl, where R = CH3, C6H5, 4-CH3OC6H4, 4-NO2C6H4; n = 2, 3; and R' = CH3, C2H5, or i-C3h7. We also prepared 4-BrC6H4C(=NOH)S(CH2)2N(C2H5)2.HCl and 4-CH3OC6H4C(=O)C(=NOH)S(CH2)2N(C2H5)2.CH3I for comparison. The alpha-ketothiohydroximates exhibit oxime acid dissociation constants (pKa) in the range 6.9 to 8.4, bracketing the value of pKa = 7.9, believed to be optimal for acetylcholinesterase reactivation. The compounds are also good nucleophiles; bimolecular rate constants (kn) for reaction with p-nitrophenyl acetate follow the expression log (kn) = 6.7 - 0.69(14 - pKa = The reactivation of (diisopropylphosphoryl)acetylcholinesterase is highly dependent on the alpha-ketothiohydroximate structure: 4-h incubation of inhibited enzyme at pH 7.6, 25 degrees C, with 1 x 10(-3) M 4-CH3OC6H4C(=O)C(=NOH)S(CH2)3N(CH3)2.HCl gives no detectable restoration of activity, whereas 4-CH3OC6H4C(=O)C(=NOH)S(CH2)2N(C2H5)2.HCl restores inhibited enzyme activity to 58% of control under identical conditions. With alpha-ketothiohydroximate in excess over inhibited enzyme, the kinetics of reactivation are governed by an equilibrium constant (Kr) for binding alpha-ketothiohydroximate to the inhibited enzyme and a nucleophilic displacement rate constant (kr) for attack on phosphorus.

Cholinesterase Inhibitors↗
PubMed1978

Naloxone and intestinal motility.

It was supposed that the inhibition of intestinal peristalsis seen in animals and humans after abdominal surgery might be related to the release of endorphins, endogenous opiate receptor agonists, caused by the surgical stress and pain. However, naloxone, a potent morphine and endorphin antagonist, failed to block this peristaltic inhibition in rats, which leaves the mechanism of this inhibition, and thus the function of intestinal endorphins, still very much in doubt.

Animals↗