Draft Hazard Identification of the Developmental and Reproductive Toxic Effects of Benzene
PREFACE
The Safe Drinking Water and Toxic Enforcement Act of 1986 (Proposition 65, California Health and Safety Code 25249.5 et seq.) requires that the Governor cause to be published a list of those chemicals "known to the state" to cause cancer or reproductive toxicity. The Act specifies that "a chemical is known to the state to cause cancer or reproductive toxicity if in the opinion of the state’s qualified experts the chemical has been clearly shown through scientifically valid testing according to generally accepted principals to cause cancer or reproductive toxicity." The lead agency for implementing Proposition 65 is the Office of Environmental Health Hazard Assessment of the California Environmental Protection Agency. The "state’s qualified experts" regarding findings of reproductive toxicity are identified as members of the Developmental and Reproductive Toxicant Identification Committee of the Office of Environmental Health Hazard Assessment’s Science Advisory Board (22 CCR 12301).
During a public meeting held in Sacramento, California, on May 12, 1995 the Committee selected benzene as a candidate for evaluation and requested that OEHHA staff prepare a review of the scientific evidence relevant to the reproductive toxicity of this agent. This draft document, which was released to the Committee and the public on September 5, 1997, responds to that request. While this hazard identification document does not provide dose-response evaluation, exposure assessment, or determination of allowable or safe exposure levels, the document does provide information which may be useful in such appraisals.
A public meeting of the Committee will be held December 9, 1997, in Sacramento, California. Following discussion and Committee deliberation, the Committee may determine whether or not benzene "has been clearly shown through scientifically valid testing according to generally accepted principles" to cause reproductive toxicity or may defer action.
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TABLE OF CONTENTS |
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| PREFACE | 2 |
| A. Abstract | 5 |
| B. Introduction | 7 |
| B.1. Chemical structure and main physical characteristics | 7 |
| B.2. Regulatory history | 7 |
| B.3. Exposure information | 7 |
| B.4. Pharmacokinetics | 9 |
| B.4.1. Absorption | 9 |
| B.4.2. Distribution | 10 |
| B.4.3. Metabolism | 11 |
| B.4.4. Elimination and excretion | 14 |
| B.5. Non-DART toxicities | 15 |
| B.5.1. Human non-DART toxicities | 15 |
| B.5.2. Experimental animal non-DART toxicities | 16 |
| B.5.3. Benzene metabolites and non-DART toxicities | 21 |
| C. Developmental Toxicity | 22 |
| C.1. Human developmental toxicity studies. | 22 |
| C.1.1. Fetal growth | 23 |
| C.1.2. Spontaneous abortion and perinatal mortality | 25 |
| C.1.3. Birth defects | 28 |
| C.1.4. Childhood leukemia | 30 |
| C.2. Animal developmental toxicity studies | 31 |
| C.2.1. Inhalation exposure during embryonic development: fetal growth retardation | 31 |
| Rats | 31 |
| Mice | 32 |
| Rabbits | 33 |
| Maternal toxicity | 33 |
| C.2.2. Inhalation exposure during embryonic development: gross, soft tissue and skeletal findings | 34 |
| C.2.3. Oral administration during embryonic development | 35 |
| C.2.4. Injection during embryonic development | 35 |
| C.2.5. Interaction of benzene with other agents during embryonic development | 36 |
| C.2.6. Transplacental genotoxicity and carcinogenicity | 36 |
| C.2.7. Transplacental hematopoietic toxicity | 37 |
| C.3. Developmental toxicity: Other relevant data | 41 |
| C.3.1. Distribution and metabolism in pregnant females and conceptuses | 41 |
| C.3.2. Mechanism(s) of benzene developmental toxicity | 45 |
| C.3.2.1. Active agent | 45 |
| C.3.2.2. Biological mechanisms of action | 47 |
| C.4. Integrative evaluation | 47 |
| D. Female Reproductive Toxicity | 54 |
| D.1. Human female reproductive toxicity studies | 54 |
| D.2. Animal female reproductive toxicity studies | 56 |
| D.2.1. Fertility | 56 |
| D.2.2. Reproductive organ toxicity | 57 |
| D.3. Female reproductive toxicity: Other relevant data | 58 |
| D.3.1. Distribution and metabolism in females | 58 |
| D.3.2. Chromosomal aberrations and related effects of benzene metabolites | 58 |
| D.3.3. Effect of benzene on noradrenergic nerves of ovaries and uterus | 59 |
| D.4. Integrative evaluation | 64 |
| E. Male Reproductive Toxicity | 64 |
| E.1. Human male reproductive toxicity studies | 64 |
| E.1.1. Fetal growth | 64 |
| E.1.2. Spontaneous abortion and perinatal mortality | 65 |
| E.1.3. Childhood leukemia | 67 |
| E.2. Animal male reproductive toxicity studies | 68 |
| E.2.1. Effects on sperm | 69 |
| E.2.2. Fertility/dominant lethal | 69 |
| E.2.3. Reproductive organ pathology | 70 |
| E.3. Male reproductive toxicity: Other relevant data | 71 |
| E.3.1. Distribution and metabolism in males | 71 |
| E.3.2. Chromosomal aberrations and related effects of benzene metabolites | 71 |
| E.4. Integrative evaluation | 72 |
| F. Summary | 77 |
| F.1. Developmental Toxicity | 77 |
| F.2. Female Reproductive Toxicity | 77 |
| F.3. Male Reproductive Toxicity | 77 |
| G. References | 78 |
Abstract
Exposures to benzene occur in connection with auto exhaust, auto fueling, tobacco smoke, and, in occupational settings, through its use as a chemical intermediate and as a component of petroleum products. Known toxic effects of benzene in humans include induction of myeloid leukemia and aplastic anemia. Benzene metabolites are clastogenic and target hematopoietic precursor cells.
There are a number of studies of the consequences of benzene exposure during organogenesis in mice, rats and rabbits, many of which used the inhalation route, which is the most common route of exposure for humans. The animal studies have consistently found developmental retardation as reflected in fetal weight and skeletal ossification at term. These effects occurred in the absence of reported maternal toxicity at some benzene concentrations. In mice, benzene also caused clastogenic effects and altered populations of hematopoietic precursors in the fetus when administered to the dam.
Relevant human studies have examined pregnancy outcome in relation to maternal occupational exposure to benzene, usually as one of a number of organic solvents, or environmental exposure to benzene as one of a number of contaminants. In case-control studies investigating maternal exposure to benzene as one of a number of concurrent exposures, there were elevated odds ratios, though most were not statistically significant, associated with adverse effects on fetal growth (preterm delivery), fetal loss (stillbirth), and birth defects (neural tube and major cardiac defects), as well as childhood leukemia. More definitive studies with assessment of benzene-specific exposure are needed to evaluate the suggested associations.
Female reproductive toxicity was not reported in the few relevant studies in the animal literature. However, in human studies, consistent reports of abnormal menstruation and excessive blood loss during childbirth in women occupationally exposed to benzene have been identified in 3 cross-sectional studies and in case series and case reports. More definitive studies with accurate assessment of benzene-specific exposure are needed to further evaluate the associations suggested by these studies.
Male reproductive toxicity studies in animals have reported benzene-induced damage to testes and sperm, including chromosomal damage. Dominant lethal effects were not reported in available rat and mouse studies. In humans, associations have been reported between paternal occupational benzene exposure and both fetal growth effects and fetal loss; a case-control study reported statistically significant elevated risks of small-for-gestational-age infants and stillbirth, while a cohort study found nonsignificant elevated risks of spontaneous abortion. Of 2 case-control studies of paternal benzene exposure and risk of childhood leukemia and non-Hodgkin’s lymphoma, the more recent study with better exposure assessment reported a statistically significant association while the earlier one failed to find such an association. Studies with accurate assessment of benzene-specific exposure are needed to evaluate the association between pre-conceptional paternal exposure to benzene and childhood leukemia.
Biological plausibility for some benzene developmental and male reproductive effects can be inferred from benzene effects on chromosomes and hematopoietic cells. There has been no direct inquiry into the mechanism of delayed intrauterine development effects. The data appear consistent with both direct effects of benzene and with effects of benzene metabolites.
- Benzene