Human Developmental Toxicants - Part 5 doc

TABLE 1 Hearing Deficits Recorded in Offspring Following Maternal Treatment of Streptomycin during Pregnancy Ref... Hearing loss in the child following streptomycin administration during

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INTRODUCTION

Streptomycin is an aminoglycoside antibiotic used therapeutically as an antitubercular agent It isalso used as part of combination therapy for treatment of streptococcal or enterococcal endocarditis,plague, tularemia, and brucellosis It is produced by the soil actinomycete Streptomyces griseus,and several salt forms have been formulated for therapeutic use from synthesized material Thedrug is used in both human and veterinary therapeutics Its mechanism of action is by inhibition

of bacterial protein synthesis by binding directly to the 30S ribosomal subunits, causing a faultypeptide sequence to form the protein chain (Lacy et al., 2004) The drug is known by its genericname as well as by a variety of trade names It has a pregnancy category of D, due largely to itsototoxic properties (see below)

DEVELOPMENTAL TOXICOLOGY

A NIMALS

The drug has been studied by the pertinent human route (intramuscular) in the guinea pig, mouse,and rabbit Guinea pigs injected with up to 100 mg/kg/day late in gestation evidenced no develop-mental toxicity (Riskaer et al., 1952) Mice given 500 mg/kg/day during 5 days of the organogenesisperiod had no overt developmental toxicity, but about 20% of the fetuses had subtle microscopic

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100 Human Developmental Toxicants

brain alterations (Ericson-Strandvik and Gyllensten, 1963) In rabbits, an unquantitated dose duced no developmental toxicity (Nurazyan, 1973) Inner ear damage pertinent to this discussion(see below) was recorded postnatally in mice given 250 mg/kg/day streptomycin on gestationaldays 12 to 18 by the intraperitoneal route (Nakamoto et al., 1985)

pro-H UMANS

In the human,the aminoglycosides are well-established ototoxins in adults Ototoxicity has alsobeen recorded with streptomycin during pregnancy Approximately 40 cases were published onthis condition (a malformative and functional deficit), and the pertinent reports are tabulated inTable 1

Hearing deficits resulted from lesions varying from vestibular dysfunction and cochlear damage

to social hearing deficits related to structural damage of the eighth cranial nerve Particularly affectedwas high-tone sensorineural hearing loss outside the speech frequencies The deficit has no specificpregnancy-specific relationship, nor, apparently, an association with dose level (the therapeutic doselevel ranges from 75 mg/kg/week up to 4 g/week maximum) No congenital malformations havebeen attributed to the drug from larger studies of antitubercular drugs (Marynowski and Sianoz-Ecka, 1972; Heinonen et al., 1977; Czeizel et al., 2000) Likewise, no other class of developmentaltoxicity (growth retardation or death) has been associated with the congenital eighth nerve lesion.Other aminoglycosides for which cases of fetal ototoxicity were recorded include dihydrostrepto-mycin and kanamycin, totaling about 28 cases (Schardein, 2000) One group of experts placed themagnitude of teratogenic risk (for deafness) due to streptomycin as being small (Friedman andPolifka, 2000) Other investigators placed the incidence of inner ear defects as 1:6 (Snider et al.,1980), as 1:10 (Ganguin and Rempt, 1970), and as 1:12 (Schardein, 2000) of those exposed Reviews

on the subject of aminoglycoside ototoxicity during development include those by Warkany (1979)and Snider et al (1980)

TABLE 1 Hearing Deficits Recorded in Offspring Following Maternal Treatment of Streptomycin during Pregnancy

Ref.

Leroux, 1950 Sakula, 1954 Kreibich, 1954 Bolletti and Croatto, 1958 Rebattu et al., 1960 Lenzi and Ancona, 1962 Kern, 1962

Robinson and Cambon, 1964 Conway and Birt, 1965 Matsushima, 1967 Rasmussen, 1969 Varpela et al., 1969 Khanna and Bhatia, 1969 Ganguin and Rempt, 1970 Nishimura and Tanimura, 1976 Heinonen et al., 1977 Donald and Sellers, 1981 Donald et al., 1991

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Streptomycin 101

CHEMISTRY

Streptomycin is a human developmental toxicant of very large size It is highly hydrophilic with

a high polar surface area Streptomycin can act as both a hydrogen bond donor and acceptor Thecalculated physicochemical and topological properties are shown in the following

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Scand J Infect Dis 32: 309–313.

Donald, P R and Sellers, S L (1981) Streptomycin ototoxicity in the unborn child S Afr Med J 60: 316 Donald, P R., Doherty, E., and Van Zyl, F J (1991) Hearing loss in the child following streptomycin administration during pregnancy Cent Afr J Med 37: 268–271

Ericson-Strandvik, B and Gyllensten, L (1963) The central nervous system of foetal mice after administration

of streptomycin Acta Pathol Microbiol Scand 59: 292–300

Friedman, J M and Polifka, J E (2000) Teratogenic Effects of Drugs A Resource for Clinicians (TERIS), Second ed., Johns Hopkins University Press, Baltimore, MD.

Ganguin, G and Rempt, E (1970) Streptomycin Behandlung in der Schwangerschaft und ihre Auswirkung auf das Gehor Kindes Z Laryngol Rhinol Otol Ihre Grenzgeb 49: 496–503.

Heinonen, O P., Slone, D., and Shapiro, S (1977) Birth Defects and Drugs in Pregnancy, Publishing Sciences Group, Littleton, MA.

Kern, G (1962) [On the problem of intrauterine streptomycin damage] Schweiz Med Wschr 92: 77–79 Khanna, B K and Bhatia, M L (1969) Congenital deaf mutism following streptomycin therapy to mother during pregnancy A case of streptomycin ototoxicity in utero Indian J Chest Dis 11: 51–53 Kreibich, H (1954) Sind nach einer Streptomycin-behandlung Tuberculoser Schwangerer schadigung des Kindes zu erwarten? Dtsch Gesundheitswes 9: 177–181

Lacy, C F et al (2004) Drug Information Handbook (Pocket), 2004–2005, Lexi-Comp., Inc., Hudson, OH Lenzi, E and Ancona, F (1962) Sul problema delle lesioni dell’apparato uditivo da passaggio transplacentare

di streptomicina Riv Ital Ginecol 46: 115

Leroux, L (1950) Existe-t-ii une surdite congenitale acquise due a la streptomycina? Ann Otolaryngol (Paris)

67: 1194–1196

Marynowski, A and Sianoz-Ecka, E (1972) [Comparison of the incidence of congenital malformations in neonates from healthy mothers and from patients treated for tuberculosis] Ginekol Pol 43: 713–715 Matsushima, M (1967) A study of pulmonary tuberculosis of pregnant women Report 7 Effects of chemo- therapy during pregnancy on the fetus Kekkaku 42: 463–464.

Nakamoto, Y., Otani, H., and Tanaka, O (1985) Effects of aminoglycosides administered to pregnant mice

on postnatal development of inner ear in their offspring Teratology 32: 34B

Nishimura, H and Tanimura, T (1976) Clinical Aspects of the Teratogenicity of Drugs, Excerpta Medica, New York, pp 130, 131.

Nurazyan, A G (1973) [Distribution of antibiotics in the organism of a pregnant rabbit and its fetus].

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cochleovestib-Riskaer, N., Christensen, E., and Hertz, H (1952) The toxic effects of streptomycin and dihydrostreptomycin

in pregnancy, illustrated experimentally Acta Tuberc Pneumol Scand 27: 211–212

Robinson, G E and Cambon, K G (1964) Hearing loss in infants of tuberculous mothers treated with streptomycin during pregnancy N Engl J Med 271: 949–951.

Sakula, A (1954) Streptomycin and the foetus Br J Tuberc 48: 69–72.

Schardein, J L (2000) Chemically Induced Birth Defects, Third ed., Marcel Dekker, New York, pp 391–392 Snider, D E et al (1980) Treatment of tuberculosis during pregnancy Am Rev Respir Dis 122: 65–79 Varpela, E., Hietalahti, J., and Aro, M J T (1969) Streptomycin and dihydrostreptomycin medication during pregnancy amd their effect on the child’s inner ear Scand J Respir Dis 50: 101–109.

Warkany, J (1979) Antituberculous drugs Teratology 20: 133–138.

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21 Methimazole

Chemical name: 1,3-Dihydro-1-methyl-2H-imidazole-2-thione

Alternate names: Mercazolyl, thiamazole

CAS #: 60-56-0SMILES: C1(N(C=CN1)C)=S

INTRODUCTION

Methimazole is a thioamide chemical used therapeutically as an antithyroid agent, given for thepalliative treatment of hyperthyroidism and to control thyrotoxic crises that may accompany thy-roidectomy The drug inhibits the synthesis of thyroid hormones by blocking the oxidation of iodine

in the thyroid gland, hindering its ability to combine with tyrosine to form thyroxine and hyronine (Lacy et al., 2004) Methimazole is available as a prescription drug under the trade nameTapazole®, among other names It has a pregnancy category risk factor of D The package labelcarries a warning that the drug “can cause fetal harm when administered to a pregnant woman.”The label goes on to state that it can induce goiter and even cretinism in the developing fetus, and,

triiodot-in addition, rare triiodot-instances of congenital defects: aplasia cutis as manifested by scalp defects,esophageal atresia with tracheoesophageal fistula, and choanal atresia with absent/hypoplasticnipples (see below; see also PDR, 2002)

A NIMALS

In animal studies, methimazole has not been shown to be teratogenic However, in two species, themouse and the rat, functional behavioral effects were produced following oral dosing of the druglate in gestation through postnatal day 10 (Comer and Norton, 1982; Rice et al., 1987) Adminis-tration of methimazole in low doses to the rabbit throughout the gestational period did not elicitany developmental or maternal toxicity (Zolcinski et al., 1964)

H UMANS

In humans, methimazole is associated with malformations as described above in the package labelfor the drug Included is a peculiar, ulcer-like midline lesion of the scalp termed “aplasia cutis

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congenita,” and less commonly, esophageal atresia and tracheoesophageal fistulae (a gastrointestinaldefect), choanal atresia, and athelia (absent nipple(s)) These findings are considered components

of the “methimazole embryopathy,” and there may be other associated anomalies as well Thereported cases are tabulated in Table 1 Of these, some 28 cases had single or multiple aplasia cutis,and several had choana, esophageal atresia and tracheoesophageal fistulae, and the absence ofnipples Other classes of developmental toxicity were occasionally associated; a number of cases

of intrauterine growth retardation (IUGR) were recorded, as well as functional impairments chomotor retardation, developmental delay, and mental retardation) and death in three of thepublished cases Even though the latter effect falls within normal frequency in pregnancy, thefinding cannot be dismissed with certainty Functional behavioral deficits occurred in animal studies

(psy-as well, and this also cannot be dismissed (psy-as irrelevant Thus, except for the rather rare malformation,aplasia cutis of the scalp, many of the affected cases appeared to be otherwise normal The usualtherapeutic dose of up to 40 mg/day orally was sufficient to induce the malformations, but thedevelopmental timetable was less well defined: Most occurred in the first trimester, but at least oneresulting case had been treated in the third trimester

Functional

wall, gastrointestinal

digits, gastrointestinal

limb

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Methimazole 107

One large study evaluated 241 women who had prenatal exposure to methimazole compared

to 1089 women who were exposed to nonteratogenic drugs (diGianantonio et al., 2001) Theyfound no major malformations or abortions but a higher incidence of choana and esophagealatresia between the third and seventh gestational weeks in the methimazole-exposed group than

in the controls

It should be stated that in several large studies, researchers found no association of methimazolewith scalp defects (Momotani et al., 1984; Van Dijke et al., 1987) Researchers who conductedanother study found no effects on somatic growth, intellectual development, or thyroid functioncaused by use of methimazole (Messer et al., 1990) Lack of effect on intellectual development bythe drug was also reported by other investigators (Eisenstein et al., 1992) One group of respectedclinicians considered the scalp defects rare but definitely related to treatment (Shepard et al., 2002),and another group found the magnitude of teratogenic risk to be minimal to small (Friedman andPolifka, 2000) Goiters in the newborn have not been a major finding, although several cases wererecorded (Warkany, 1971; Refetoff et al., 1974) The closely related drug and parent compound ofmethimazole, carbimazole, was also associated with similar malformations in several cases, andthyroid effects in a number of other reports (Schardein, 2000)

Several reviews exist of methimazole treatment and resulting developmental effects (Mandel

et al., 1994; Wing et al., 1994; Clementi et al., 1999; Diav-Citrin and Ornoy, 2002)

CHEMISTRY

Methimazole is a small heterocyclic compound with a relatively low polar surface area It is ofaverage hydrophobicity compared to the other compounds within this compilation It can partic-ipate in hydrogen bonding The calculated physicochemical and topological properties are asfollows

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T OPOLOGICAL P ROPERTIES (U NITLESS )

Farine, D et al (1988) Elevated α -fetoprotein in pregnancy complicated by aplasia cutis after exposure to methimazole Obstet Gynecol 71: 996

Ferraris, S et al (2003) Malformations following methimazole exposure in utero: An open issue Birth Defects Res (A) 67: 989–992.

Friedman, J M and Polifka, J E (2000) Teratogenic Effects of Drugs A Resource for Clinicians (TERIS), Second ed., Johns Hopkins University Press, Baltimore, MD.

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Martin-Denavit, T et al (2000) Ectodermal abnormalities associated with methimazole intrauterine exposure.

Am J Med Genet 94: 338–340.

Martinez-Frias, M L et al (1992) Methimazole in animal feed and congenital aplasia cutis Lancet 339: 742–743.

Messer, P M., Houffa, B P., and Olbricht, T (1990) Antithyroid drug treatment of Grave’s disease in pregnancy: Long-term effects on somatic growth, intellectual development and thyroid function of the offspring Acta Endocrinol (Copenh.), 123: 311–316

Milham, S (1985) Scalp defects in infants of mothers treated for hyperthyroidism with methimazole or carbimazole during pregnancy Teratology 32: 321

Milham, S and Elledge, W (1972) Maternal methimazole and congenital defects in children Teratology 5:

PDR®(Physicians’ Desk Reference ® ). (2002) Medical Economics Co., Inc., Montvale, NJ.

Ramirez, A et al (1992) Esophageal atresia and tracheoesophageal fistula in two infants born to hyperthyroid women receiving methimazole (Tapazole) during pregnancy Am J Med Genet 44: 200–202 Refetoff, S et al (1974) Neonatal hypothyroidism and goiter of each of two sets of twins due to maternal therapy with antithyroid drugs J Pediatr 85: 240–244

Rice, S A., Millan, D P., and West, J A (1987) The behavioral effects of perinatal methimazole administration

in Swiss Webster mice Fundam Appl Toxicol. 8: 531–540.

Sargent, K A et al (1994) Apparent scalp–ear–nipple (Findlay) syndrome in a neonate exposed to azole in-utero Am J Hum Genet 55 (Suppl.): A312

methim-Schardein, J L (2000) Chemically Induced Birth Defects, Third ed., Marcel Dekker, New York, p 468 Shepard, T H et al (2002) Update on new developments in the study of human teratogens Teratology 65: 153–161.

Shikii, A et al (1989) A case of hydrops fetalis, minor anomalies and symptomatic West syndrome born to

a mother with Basedow disease and thiamazole treatment Teratology 40: 663

Tanaka, S et al (1989) Three cases of neonatal congenital anomalies associated with maternal ism Teratology 40: 673–674.

hyperthyroid-Van Dijke, C P., Heydeendael, R J., and de Kleine, M J (1987) Methimazole, carbimazole, and congenital skin defects Ann Intern Med 106: 60–61.

Vogt, T., Stolz, W., and Landthaler, M (1995) Aplasia cutis congenita after exposure to methimazole: A causal relationship? Br J Dermatol 133: 994–996

Warkany, J (1971) Congenital Malformations Notes and Comments Year Book Medical Publishers, Chicago,

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Zolcinski, A and Heimrath, T (1966) Fetal damage following treatment of the pregnant woman with a thyreostatic drug Zentralbl Gynaekol 88: 218–219.

Zolcinski, A., Heimrath, T., and Rzucidlo, Z (1964) Effect of thiamizole (methimazole) on fetal development

in rabbits Ginekol Pol 35: 593–596.

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22 Ethylene Oxide

Alternate names: Dimethylene oxide, 1,2-Epoxyethane

CAS #: 75-21-8SMILES: C1CO1

INTRODUCTION

Ethylene oxide is a colorless gas used in the production of ethylene glycol, acrylonitrile, andnonionic surfactants It is also used as a fumigant for foodstuffs and textiles, as a sterilizing agentfor surgical instruments, and as an agricultural fungicide (The Merck Index, 2001) It is readilyabsorbed after dermal or inhalational exposure (Friedman and Polifka, 2000) The permissibleoccupational exposure limit is 1 ppm (8 h time-weighted average) (ACGIH, 2005) It has severaltrade names — Anproline®, Oxidoethane®, and Oxirane®, among others — and it is often referred

to by its chemical name

A NIMALS

In animal studies, ethylene oxide displays developmental toxicity attributes in mice and rats whenexposure is through the inhalational route In the mouse, the chemical caused malformations,reduced fetal weight, and embryolethality when a regimen of 1200 ppm for single intervals rangingfrom 1 up to 25 h after mating was employed (Rutledge and Generoso, 1989) The mechanism ofthis early effect could involve a nonmutational imprinting process that causes changes in geneexpression (Katoh et al., 1989) In rats, the chemical was not teratogenic, at least by the inhalationalroute of exposure, but it was maternally toxic and reduced fetal body weight and increased fetaldeath over the range of 100 to 1200 ppm given over a 10-day period during organogenesis (Snellings

et al., 1979; Saillenfait et al., 1996) Dosages of 9 to 36 mg/kg/day by the intravenous route given

to rabbit does for 4 or 9 days during organogenesis elicited embryotoxicity in their young (Kimmel

et al., 1982)

H UMANS

In the human, developmental toxicity apparently has been limited to spontaneous abortion, as shown

in Table 1 The evidence is not strong, but negative evidence has not been forthcoming to dispelthe association However, several reports have been critical of the methodology and conclusions

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made by the cited investigators (Austin, 1983; Gordon and Meinhardt, 1983; Olsen et al., 1997)

No other developmental toxicity was apparent from analysis of the limited published studies.One group of experts places the magnitude for spontaneous abortion as minimal to small(Friedman and Polifka, 2000)

Chemical factory workers

(0.55 ppm)

factory workers

Yakubova et al., 1976 Hospital staff engaged in sterilizing

materials (0.1–0.5 ppm)

hospital staff (17 versus 6%)

Hemminki et al.,

1982, 1983 Dental assistants (exposure data not

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