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https://ntp.niehs.nih.gov/go/128

Developmental & Reproductive Toxicity

Mitosis of embryo under microscope

Study Overview

Study: Developmental toxicity, reproductive toxicity
Species: Rats, mice, rabbits, zebrafish

Description

NTP has developed a range of techniques and testing regimes to evaluate the potential of environmental and occupational substances to affect development and damage reproductive systems. Testing is focused on the following areas of study.

Prenatal Developmental Toxicity Studies

The prenatal developmental toxicity study (also known as embryo-fetal developmental study, teratology study, or Segment II study) is undertaken to identify substances that may pose a risk to the developing fetus if pregnant women are exposed. Regulatory agencies use the results of well-conducted animal studies to help set human exposure guidelines. The experimental protocols, in general, are outlined by EPA Health Effects Test Guidelines OPPTS 870.3700 and ICH S5(R2).

Prenatal developmental toxicity studies are typically carried out using rodent models. Substances are tested in pregnant animals for their potential to cause birth defects and other signs of toxicity during embryo-fetal development. If a substance induces an adverse effect in the offspring, a second species may be used to confirm this response. Pregnant females are usually exposed to the substance from implantation, that is, the attachment of the embryo in the uterus (day 6 of the embryo development in the rodent) to the day before birth. However, they may be exposed to the substance throughout pregnancy. This testing paradigm can also be used within a larger study to assess multigenerational responses. See Modified One-Generation study design for details.

Reproductive Studies

NTP has developed a range of techniques and testing regimes for evaluating the potential toxic effects of exposure to environmental and occupational substances on the reproductive system. These studies are carried out primarily using rodent models. Characterization of these potential effects on reproduction are now typically assessed using the Modified One-Generation study design.

Modified One-Generation Studies

Historically, NTP evaluated the potential for a substance to cause reproductive harm via a multigenerational reproduction experimental design. NTP has modified this study design to use fewer animals, while generating information on the effects of substances on prenatal development, postnatal development, and reproduction.

NTP's Modified One-Generation Reproductive study design employs pregnant animals with dosing beginning at implantation and continuing throughout gestation and lactation. At weaning, the offspring are administered the test substance at the same dose level as their respective mother and are subsequently assigned to a number of different cohorts including:

  • a subchronic toxicity cohort – to evaluate target organ toxicity, pathology, clinical pathology on subchronic toxicity, that is, of moderate duration and not long-term.
  • a teratology cohort – to evaluate prenatal development, that is, development before birth. Teratology specifically refers to the scientific study of congenital abnormalities and abnormal development of organs or tissues that impact function and vitality.
  • a littering cohort – to evaluate breeding and littering to assess potential effects in the subsequent generation.
  • a developmental neurotoxicity (DNT) cohort – to evaluate neurobehavioral end-points and neurohistopathology. Neurotoxicity refers to a form of toxicity when a substance effects the central or peripheral nervous system, and neurohistopathology is the study of changes caused by disease at the cellular level in neural tissues.

Studies Using Zebrafish Embryos

The small size and rapid development of the zebrafish make it a useful vertebrate model for assessing potential effects of substances on development in a mid- to high-throughput manner. However, deficits in several key areas hinder the broader adoption of the zebrafish model for toxicological screening, including consistency of experimental protocol elements; understanding of mechanisms of substance absorption, distribution, metabolism, and excretion in zebrafish; and consistency of informatics approaches used for classification of outcomes. NTP established the Systematic Evaluation of the Application of Zebrafish in Toxicology (SEAZIT) program to enable the broader adoption of zebrafish for toxicological screening.

Levels of Evidence Criteria

Levels of Evidence for Developmental Toxicity

NTP describes the results of individual studies for test substances, and notes the strength of the evidence for conclusions regarding each study. Given that developmental events are intertwined in the reproductive process, effects on developmental toxicity may be detected in reproductive studies. Evaluation of such developmental effects should be based on the NTP Criteria for Levels of Evidence for Developmental Toxicity. The Levels of Evidence are divided into five categories.

Categories for positive experimental results:

Clear Evidence of Developmental Toxicity
Some Evidence of Developmental Toxicity

Category for uncertain experimental results:

Equivocal Evidence of Developmental Toxicity

Category for no observable effects:

No Evidence of Developmental Toxicity

Category for experiments that cannot be evaluated because of major flaws:

Inadequate Study of Developmental Toxicity

Levels of Evidence for Reproductive Toxicity

NTP describes the results of individual studies for test substances, and notes the strength of the evidence for conclusions regarding each study. Evaluation of reproductive effects are based on the NTP Criteria for Levels of Evidence for Reproductive Toxicity. The Levels of Evidence are divided into five categories.

Categories for positive experimental results:

Clear Evidence of Reproductive Toxicity
Some Evidence of Reproductive Toxicity

Category for uncertain experimental results:

Equivocal Evidence of Reproductive Toxicity

Category for no observable effects:

No Evidence of Reproductive Toxicity

Category for experiments that cannot be evaluated because of major flaws:

Inadequate Study of Reproductive Toxicity

Non-Cancer Evaluation Criteria

NTP is working to bring the same rigorous standards used for categorizing the outcomes of its cancer studies to its non-cancer studies (developmental, immunotoxicity, and reproductive studies).

Non-Cancer Evaluation Categories

NTP uses the following five categories to describe the strength of the evidence for non-cancer study findings:

Clear Evidence
Some Evidence
Equivocal Evidence
No Evidence
Inadequate study

Specifications & Guidance

Abstracts & Reports

Note on Accessibility: Persons with disabilities or using assistive technology may find some documents are not fully accessible. For assistance, email us or use our contact form and identify the documents/pages for which access is required. We will assist you in accessing the content of these files. NIEHS has helpful information on accessibility.

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Abstracts and Reports for Developmental & Reproductive Toxicity
Abstract Full Text Report Title Year Type
DART-04 Draft (2MB) Development Toxicity Evaluation of Dimethylaminoethanol (CASRN 108-01-0) Administered in Female Harlan Sprague-Dawley Rats on Gestational Days 6 to 20 N/A Developmental & Reproductive Toxicity
DART-03 Draft (871KB) Development Toxicity Evaluation of Vinpocetine (CASRN 42971-09-5) Administered in Female Harlan Sprague-Dawley Rats on Gestational Days 6 to 20 and New Zealand White Rabbits on Gestational Days 7 t0 28 N/A Developmental & Reproductive Toxicity
DART-02 Draft (2MB) Development Toxicity Evaluation of 4-Methylcyclohexanemethanol (CASRN 34885-03-5) Administered in Female Harlan Sprague-Dawley Rats on Gestational Days 6 to 20 N/A Developmental & Reproductive Toxicity
DART-01 Draft (2MB) Development Toxicity Evaluation of Tris(Chloropropyl)phosphate (CASRN 13674-84-5) Administered in Female Harlan Sprague-Dawley Rats on Gestational Days 6 to 20 N/A Developmental & Reproductive Toxicity

Note: Abstracts for studies conducted between 1985 and 2012 are available on the Study Abstracts page. These studies have not been evaluated by the levels of evidence criteria for developmental, reproductive, or immunotoxicity established by NTP in March 2009. Because this is not a comprehensive list, email us or use our contact form to inquire about other studies.

Short-Term Reproductive and Developmental Toxicity Studies of Water Disinfection By-Products

These studies assessed the general reproductive and developmental toxicities of several water disinfection by-products in rats using the Short Term Reproductive and Developmental Toxicity Screening design (Harris, et al, 1992). The study approach sought to identify the body systems that are the most sensitive to exposure from these substances.

The water disinfection by-products studies focused on the following:

  • Development
  • Female reproduction
  • Male reproduction
  • Various somatic organs or processes

The data generated from these studies identified water disinfection by-products (and related compounds) that require further investigation.

Protocol

This short-term test for reproductive and developmental toxicity provided preliminary data on the toxicity of substances about which little or no data existed.

Mice were mated for 3 days prior to substance exposure to produce time-mated females for gestational exposure and to ascertain fertility of the untreated males. The group of time-mated females were treated during gestation days (GD) 8-14 and allowed to litter for observations through postnatal day (PND) 4. Observations included:

  • Pup number and body weights on PND 0, 1, and 4
  • Number of uterine implantation sites on PND 4

A second group of females were dosed daily for 19 days. After 7 days, these females were housed with males who had been treated for 5 days prior to the second mating. Daily chemical dosing continued during the 5-day cohabitation.

This second group of females were humanely euthanized after 19 days of treatment. The following data were recorded:

  • The number of live fetuses
  • The number of dead fetuses
  • The number of implantation sites

After 17 days of dosing, the males were humanely euthanized and their reproductive systems were evaluated. Observations included:

  • Organ weights
  • Testicular histology
  • Total epididymal sperm counts and motility