Document NQm5GvKgXVbgLyo0g93QNE3g

Effect of environmental factors on drug metabolism: Decreased plasma half-life of antipyrine in workers exposed to chlorinated hydrocarbon insecticides In twenty-six men occupationally exposed to a mixture of insecticides, mainly lindane and DDT, antipyrine had a significantly shorter plasma half-life than in 33 control subjects. " ' If the mechanism is the sarxe as that in annuals, these studies indicate that insecticides can induce microsomal drug metabolism in matt. Birgitta Kolmodin, Daniel l. AzarnofT.* and Folke Sjoqvist Stockholm, Sweden Department of Occupational Medicine, Xssional Institute of Occupational Health, and Department or Pharmacolcgj (Division cf Clinical Pharmacology), Karolinska Institutet Induction of various drug-metabolizing enzvmes bv chemicals is a well-known phenomenon in experimental animals. Hepatic microsomal hydroxylating-enzvme activity can be nonspecincally In duced by a vast number of drugs and chlorinated insecticides. *3* 13 In 1963. Hart and co-workers14 reported a shorten ing of hexobarbital sleeping times in rats housed in quarters which had been sprayed with chlordane. This phenomenon was paralleled by an increase of hepatic endoplasmatic reticulum and microsomal oxi dative drug-metabolizing enzyme activity. Subsequently, chronic feeding of 1,1-bis (chlorophenvl) trichloroethane (DDT) and its analogues produced similar and Supported by Grant CM 1397S from the National Institutes of Health, Bethesda, Md, Received for publication April 7, 1969. Accepted for publication Mar 29, 1969, Fillbright scholar. Permanent address: University' of Kansas Medical Center, Kansas City, Kansas. 638 long-lasting effects,13*13 which were ob tained by use of a diet containing only 5 parts per million of DDT, a level which can be found in some human food resi dues.33 Increased activity of hepatic micro* somal oxidative drug metabolism in the rat was also produced by 1,1-bis (chloiopbenyl) dichloroethane (DDD), perthane, kd- thane, chlordane, and methoxychlor admin*: istration.13 In the mouse, on the other band. DDD inhibits oxidative microsomal drug metabolism.13 The organophosphorus pesty, cides also inhibit hexobarbital metabolism in the mouse.13 - One feasible way to assess the activity of liver microsomal enzymes in man is study the elimination rate of drugs which are: (1) metabolized in the liver, (2) excreted to a great extent unchanged Jty the kidney, and (3) not appreciably boumj to plasma proteins. Antipyrine fulfills these criteria. It is rapidly absorbed, only 5 p**. cent is excreted unchanged, in the urinft th, mi co UE M D. isc w* 'c dr P> d: $ er of b, fr st th e> i; v & Effects of insecticides ^aad the remainder is metabolized in the liver. Its metabolism includes hydroxyla- ~ tion hi the 4 position of the pyrazolone ring ^ith subsequent conjugation.2 Recent in- -fTyestigations indicate that hvdroxvlation of '*the CH3-group in the 3 position also takes X place." The plasma half-life of antip\Tine 1 - in man is reported to vary between 5 to 17 Shows," indicating marked individual dif ferences. It is known that the storage of ehlormated insecticides is lower in a general population than in occupationally exposed . workers.*'ls'15 To our knowledge, no data : are available on the effect of exposure to insecticides on drug metabolism in man. The purpose of this investigation was to study whether long-term exposure to in secticides changes the plasma half-life of antipyrine. X Material and methods Subjects. After a thorough discussion of the purpose and risks involved, 26 Swedish male workers from a company handling the commercial application of insecticides vol untarily participated in this investigation. Most of them were exposed to a mixture of DDT, chlordane, and lindane (the gamma tsomer of benzene hexachloride). and some ...were also exposed to malathion, nankor ,, {dimethyl-2,4,5-trichlorophenyl -phosphothionate), diazinon (0.0-diethyl-0-2-isopro' Pjd-4-methylpyrimidvl-6- thiophosphate), , DDVP (dimethyI-2,2-dichIorovinviphos.. P^te), and pentachlorophenol. The work- bandied the compounds in the form aerosls and mists (principle solvents J kerosene-like products) weekly or as as daily. Protective measures lave been taken, but a review of medical records indicated that some m the form of inhalation and skin /pbon was possible, as was reported -^Lp^kam* and Hayes and Curley.1* *contro^ objects were 15 men and fvr;'Vornet, of Swedish descent, mainly of- personnel from the same firm. All sub^VCre ^rom *be same geographical Volunteers with a history of allergic reactions were excluded and no subject ad mitted any drug consumption during the 2 months preceding the investigation. They were specifically questioned concerning their use of barbiturates as well as other hvpnotics and drugs which are known to affect drug metabolism. Methods. Antipyrine was given orally in gelatin capsules in a dose of 10 or 15 mg. per kilogram. The initial volunteers were given 15 mg. per kilogram; but when it was determined that 10 mg. per kilogram could be used satisfactorily, the dose was reduced for the remaining subjects to mini mize the possibility of adverse reactions. A blood sample for a blank reading was obtained prior to the drug administration and was followed by samples drawn in heparinized tubes 3,6,9, and 12 hours there after. The blood level of antipyrine was. measured according to the method of Brodie and associates* except for the ex traction which was done with methylene chloride. Standard curves were prepared with plasma from the blood bank at the Karolinska Hospital. Samples were ana lyzed in duplicate. The half-life of anti pyrine in each individual was determined from the linear portion of a plot of the plasma values on semilogarithm paper. Unless otherwise noted significance was determined by the Wilcoxon Rank Sum test.2'10 Results For the group' exposed to insecticides, the half-life of antipyrine was normally dis tributed with a mean of 7.7, standard de viation of 2.6, a median of 7.5, and a range of 2.7 to 11.7 hours (Fig. 1). In the control group, there was a skew distribution, with a mean of 13.1, standard deviation of 7.5, a median of 11.5, and a range of 5.2 to 35.0 hours. In this group, a half-life greater than 25 hours was seen in 4 persons (Fig. 1). The half-life of antipyrine in the ex posed group was significantly lower than that in the control group (0.001 <p <0.01). The half-life of antipyrine after 10 and 640 Kolmodin, Azarnoff, and Sjdqcist Ctin,icalPhan^" Fig. 1. Plasma half-life of antipvrine in subjects exposed to insecticides and nonexposed control subjects. 15 tug. per kilogram was not significantly different, as reported elsewhere.*1 Xo sex difference teas found. In the exposed group, no significant difference (p = 0.4, Stu dents t test) was found between smokers (7.6 = 2.1 S.E.) and nonsmokers v7.9 1.3 S.E. Discussion Marked individual differences in the rate of drug metabolism in man have recently been reported for a number of compounds such as tricyclic antidepressants.1-'-11 chlorpromazine,4 and phenylbutazone,17- -1 which are metabolized in the liver microsomes. The relative contribution of en vironmental versus genetic factors to these individual differences is beins debated. Based on studies in twins, Yesell*1- ** re centl*y suMggVested that the individual differences in the half-life of antr*o. *vrine and phenylbutazone were largelv genetically determined. Leri and associates1* showed that the mean Was lower and the range of the halflife of phenylbutazone was smaller in pa tients with liver disease if they were tak ing various drugs thought to induce the liver microsomal enzymes. In fact, a histcry of previous ingestion of certain drugs was more important in determining the half-life of phenylbutazone than was se vere liver disease (in the place cited). In animals, it has already been shown But low exposure to low levels of certain In secticides stimulates drug metabolism. Our observations seem to be the first to indi cate a similar effect of insecticides in maw The half-life of antipyrine was shorter in workers exposed to various insecticides than it was in control subjects, and die range of the half-life was considerably narrower in the exposed group. Thus, our data demonstrate that these environmental factors may play a role in regulating the rate of drug metabolism. In this contest it is appropriate to call attention to die stud ies by Welch and associates*4 demonstrat ing the inducing effect of smoking on 3,4benzpyrene hydroxylase activity in the hu man placenta and to the findings of Bled soe and associates1 that fallowing treatment with o,p'DDD, the urinary excretion of jS-hydroxycortisol increased in human h** ings probably as a result of an increased extra-adrenal hydroxylation of cortisol4 The enzyme-inducing effect of insecti cides on drug metabolism in has been shown to develop for a number of different microsomal drug-metabolic path ways.1*- 13 It is, therefore, of value to fa* vestigate exposed subjects regarding the metabolism of other drugs,- studying no* only disappearance rates of parent <fru*s 10 Effects of insecticides 641 but also the formation of various metabJ elites representing different pathways. Such Studies are now in progress. The mixed exposure of our subjects to a variety of insecticides makes it impossible to eval uate the effect of individual compounds. preliminary* gas chromatographic analysis of chlorinated pesticides in blood from a few of the study subjects showed an in creased level of lindane and DDT com pared with that of the control subjects. The common denominator in all exposed workers was lindane which, in comparison with DDT and chlordane, has been meagerly investigated in animals. How ever, evidence in favor of an inducing efJ feet of benzene hexachloride on drug hydroxylation has been reported in dogs1* j[and in rats. Experiments in progress* in [ this laboratory show that the metabolism of antipyrine in the isolated perfused rat isf Kver is significantly enhanced 4 days after s? a single dose of lindane (60 mg. per kilogram intraperitoneallv) compared with & that in controls. . We thank Mrs. Marie-Louise Rosenqvist and Miss Ulla Englund for technical assistance. % References sfr 1. Bledsoe, T., Island, D. P., Ney, R. L., and Liddle, G. W.: An effect of o.p'DDD on the textra-adrenal metabolism of cortisol in man, J. Clin. Endocrinol. 24:1303-1311, 1964. |_ 2.Brodie, B. B., and Axelrod, J.; The fate of wtipyrme in man, J, Pharmacol, k Exper. Therap. 98:97-104, 1950. Jk Brodie, B. B., Axelrod, J., Soberman, R., and levy, B. B.: The estimation of antipyrine in biological materials, J. Biol Chem. 179:25-29, _ . 1949. ^Cooney, A. H.: Pharmacological implications of microsomal enzvme induction, PharmacoL Rev. 19:317-366, 1967. JS- Qmney, A. H., Welch, R. M., Kuntzman, R., and Bums, J. J..- Effects of pesticides on drug j-y **4 steroid metabolism, Cun. Pharmacol, & Tberap. 8:2-10, 1967. $. H., and Marshall, J. H. L-: Plasma .,Z1- yvds of chlorpromazine and some of its rela tively non-polar metabolites in psychiatric paLife Sc. 7:9-17, 1968. 7. Dixon, IV. 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