Chemically Induced Birth Defects PDF

Preface

According to estimates, of about 3 million infants born in the United States each year, some 250,000 will have birth defects (Dwivedi and Iannacocone, 1998). In other words, of about 10,684 babies born in the United States on an average day, 781 have low birth weight, 411 are born with a birth defect, 81 die before their first birthday, and 18 die as a result of a birth defect (March of Dimes, 1998). In addition, countless lives are claimed each year through spontaneous abortion, stillbirth, and miscarriage due to defective fetal development.

Congenital anomalies rank about sixth among all causes of death in the United States, according to published data.* Some 10 times as many children die of malformations as from contagious diseases, and they account for 20% of all postnatal deaths (Mofenson et al., 1974). Furthermore, almost one-half of the children confined in hospitals are there because of prenatally acquired birth defects (Shepard, 1989). The social burden can be more fully appreciated when one considers that birth defects affect the daily lives in some way or another of 15 million persons in the United States alone, and the cost of caring for individuals with major disorders is staggering (almost $13 billion annually over 20 years ago) (Wallace, 1976). With estimates that as many as 75,000 chemicals may be in use at present and new ones added each year, the concerns over chemical and drug causation of birth defects have reached immense proportions, and show no signs of abating.

Anxieties generated by these gloomy statistics have led in recent years to implications of environmental agents as a potential source of reproductive failures and induction of congenital malformation. Witness the real or imagined claims in contemporary history of hazardous events associated with methyl mercury, alcohol, cigarette smoking, PBBs and PCBs, red dye #2, OCs, spray adhesives, DES, anesthetic gases, caffeine, 2,4,5-T, dioxin and Agent Orange, lead, Bendectin^®, cocaine, and, of course, the notorious thalidomide. 

The frequency of some types of reproductive impairment has changed in time at a rate much too rapid to be explained by genetic changes or changes in other intrinsic factors (Nisbet and Karch, 1983). Drugs and other chemicals are part of the broad spectrum of environmental factors that are known or suspected to impair reproductive success in humans, and there is at present only limited evidence that can be used to estimate their overall importance. While there are data to indicate that drugs and chemicals have substantial adverse effects on reproduction in highly exposed groups, such as smokers and drinkers, evidence that they may have such effects in the general population is scant and inconclusive. This is because it is extremely difficult, if not impossible, to investigate possible effects of widespread, low-level exposure in the environment. Thus, while it has been estimated that only a fraction of the total spectrum of defects observed in humans is due to drugs and environmental chemicals, it is highly important that all potential chemical teratogens be identified and measures taken to control use or exposure to them by pregnant women and their unborn children.

Over twenty years ago, I cited the fact that more than 1900 chemicals had been tested for teratogenicity in animals, of which about one-third were teratogenic (Schardein, 1976). My current estimate, substantiated by studies reported in this volume, is that more than 4100 chemicals have been tested to date, and again about one-third (34%) are teratogenic.

It is the purpose of the present volume to catalog the available data on drugs and chemicals with respect to their potential teratogenicity in animals and in humans. Each year, as the list of drugs available to the consumer grows and the number of environmental chemicals and pollutants increases, it becomes increasingly important to establish criteria by which agents can be accurately determined for possible hazard before public use, if birth defects are ever to be prevented. A number of other reference works have appeared on drug or chemical usage since the preparation of the second edition of this work, but no volume is available that correlates the laboratory and clinical teratogenic properties of environmental chemicals in the same manner as this book. It is hoped that the present work will serve as a useful source of reference to scientists and clinicians now and in years to come.

Justification for revising this work lies in the continuing need for identifying chemical exposures that present potential toxicity to the developing human conceptus. And while it is true that no major epidemics of birth defects have surfaced since intensive animal testing was implemented more than 30 years ago, there are hazards to be concerned about: witness the devastating effects on offspring of mothers using cocaine. Furthermore, the laboratory and clinical data this volume contains provide needed updated information on potential hazards to individuals involved in providing information and counseling to the public sector (e.g., physicians and health counselors). The addition of well over 1000 new entries to this revised edition is a clear indication of how much the information database on teratogens is growing and underscores the difficulties in accessing it in a timely fashion.

The chemicals discussed in the text include those in current use, some still considered experimental, and others now obsolete or withdrawn from use. They include chemicals to which we are exposed, either intentionally or not. This work does not include nonchemical potential sources of teratogenesis (i.e., radiation, infectious disease, and physical factors)

Sources for the information given in this volume are many. It will be most appreciated by teratologists that the task of keeping contemporaneous in the field is an extremely difficult, if not completely impossible, task. It has been estimated, for instance, that the number of new publications in the field of teratology is about 2500 per year (Wassom, 1985). Nonetheless, several sources of information in addition to the usual journal and book references are indispensable, and were of special value to me in this endeavor. The most useful of these to me currently is Tech Track® (published by NERAC®, Inc.), which provides timely listings of the contents of more than 50 scientific journals that contain material relating to the subject of developmental toxicology (teratology)

The data obtained from this and other sources are added to my personal computerized database to facilitate information retrieval.

Virtually all chemicals included are listed by generic names as an aid in identification and for consistency. For agents to which generic names have not been assigned, chemical names are used; in a few cases, specific trade names are used when this name is most commonly used. Sources for agent identity and information included in this volume are the current editions of the American Drug Index (Lippincott); USAN and the USP Dictionary of Drug Names (U.S. Pharmacopeial Convention, Inc.); The Merck Index: An Encyclopedia of Chemicals and Drugs (Merck & Co.); Martindale, The Extra Pharmacopoeia (The Pharmaceutical Press); Hawley's Condensed Chemical Dictionary (Van Nostrand Reinhold); Drug Reference Guide to Brand Names and Active Ingredients (C. V. Mosby); Physician's Desk Reference (Medical Economics Co.); Drug Facts and Comparisons (Lippincott); Pesticide Index (Unwin Bros., Ltd.); Dictionary of Chemical Names and Synonyms (Lewis); and Dictionary of Drugs, Chemical Data, Structures and Bibliographies (Chapman and Hall).

The basic layout of this work is simple and straightforward. All agents used therapeutically as medicinals or drugs are discussed under their respective area of therapeutic use (e.g., anticonvulsants, cancer chemotherapeutic drugs) in Chapters 3 through 24; the remainder of the agents, those having strictly chemical or industrial uses, are discussed in Chapters 26 through 33. The single exception is Chapter 29, which includes a few agents used therapeutically but are more logically placed in Part II because of the larger group to which they belong. The two parts are preceded by a general chapter on drug use in pregnancy (Chapter 2) and chemical exposure in pregnancy (Chapter 25), respectively. This format permits direct comparisons of agents within a given group. The first chapter of this work outlines the principles of teratogenesis as they apply to pregnancy exposure.

Teratogenic reactions tabulated in the tables in the various laboratory species are indicated +, teratogenic; +equivocally teratogenic; and -, not teratogenic. Such designations are not meant to be interpreted as the final arbiters of teratogenicity. They indicate in simple form the reaction under the specific experimental condition in the species described in the published reports. In defense of this binary designation, let me state in the strongest possible terms, that I am well aware that under the right conditions, all chemicals will elicit some measure of toxicity, be it teratogenesis or any of the other three classes of developmental toxicity. Indeed, this very aspect is emphasized throughout this work. However, the intent here is to present to the reader seeking teratologic data on a given chemical, in the simplest terms, what the published studies have demonstrated. The reactions thus represent a teratogenic effect, or equivocal one, or none at all, under the conditions or regimen employed in the cited study. Nothing more or less is intended. The reader must, of course, read the cited publications to obtain additional details beyond those provided here in the text. 

The published reports obviously vary in quality, and, since I have made subjective judgments in considering the specific experimental evidence offered, there is no certainty as to whether the assessments made are reflective of overall teratogenic potential under all conditions of use or exposure. Both old and new studies were considered for inclusion. Given the choice of a recent Good Laboratory Practices–conducted study that is scientifically sound and one that is neither, I chose the former. It should be mentioned with regard to quality of teratogenic studies that one group of investigators found that only 10% of published studies they examined of teratogenic evaluation of specific agents were conducted adequately.* This is a sad commentary, but unfortunately true, and it is this unevenness in quality of data to be evaluated that makes interpretation difficult in many instances, and even more tenuous in extrapolating to likely human hazard.

Data in this volume represent results evolving only from experimental studies in animals with treatment given in the organogenesis period, i.e., the regimen that might be expected to induceterata and other developmental toxicity under appropriate conditions. Obviously, there is a wealth of published data relating to other aspects of reproduction, for instance, in fertility and reproduction studies, perinatal and postnatal studies, and multigeneration studies. While many of these might interest the reader because they too are in the province of reproductive toxicology, the major objective of this volume is correlation of data related to the induction of malformations. Absence of certain chemicals from the presentation then, does not necessarily mean that the chemical has not been studied experimentally; it only indicates that data concerning the chemical have not been published in the context of teratogenesis. The emphasis on data from humans too has been placed on reports in which exposure to drugs or chemicals was primarily in the first trimester of pregnancy, again, the period when congenital malformations would be expected to occur were they causally associated with administration. Where pertinent to the overall presentation, I have taken license to discuss other developmental toxicity.

Data from studies in which unusual or unique methods of administration or assessment and that vary from traditional methods are not considered except when such methods impart a special meaning to the data. This is because such methods do not permit metabolism of the chemical nor do they allow placental movement. These include direct fetal injections, intra-amniotic injections, and in vitro cultures.

Discussion of experimental teratology has been limited to mammals. Three species—the mouse, the rat, and the rabbit—have been emphasized, because of their almost universal use by experimental teratologists, but less widely used species are also included. These data are correlated with the clinical human data as the major focus. For the sake of conserving space, I have included only literature citations of initial reports and those I considered most pertinent to the overall characterization of a given chemical's teratogenic potential. This treatise is not meant to be an intensive critical review of all published literature in the field of teratogenesis; it is hoped however that the work is as comprehensive in scope as any such effort could expect to be based on one experienced investigator's review of the vast body of literature representing the field of this science.

Some effort has been made in this edition to place effects in animals as much in perspective to human exposures as feasible. For example, the concern expressed for an agent with potential developmental hazards for a population of 100,000 individuals is much greater than for the same chemical to which only 100 individuals are exposed. This is done for drugs by providing information on prescription or nonprescription sales of the drug where appropriate, and direct comparisons between doses producing developmental effects in animals compared to doses taken by humans. For chemicals, production and exposure data are used in this context.

Finally, I would greatly appreciate any reader calling to my attention any outright error or inaccuracy in reporting any study cited in the interest of correct representation in future volumes.