Vulnerable People & Pesticide Exposure Windows

Populations of greatest concern for exposures to potential endocrine disruptors are pregnant women and their children (embryos, fetuses and newborns). Sensitive windows of exposure are at conception, during pregnancy, in utero, throughout early life stages (neonatal and juvenile) and during pubertal development and adolescence.

These sensitive exposure times and vulnerable populations apply to all potential areas of concern for human health but they are often associated with potential endocrine disruptors. They are taken into account by all mandatory toxicological and ecotoxicological testing for pesticides. These tests look for any adverse health effects, including those involving the endocrine system.

Sensitive Pesticide Exposure Windows

For human health, at least three studies are required to assess adverse effects of pesticides that may occur due to exposure during sensitive periods:[1] the rodent two-generation reproduction toxicology study and rodent and rabbit prenatal, developmental toxicity studies (described below). For environmental species, relevant ecotoxicological tests either address this directly by exposing all life stages (rat multi-generation reproduction studies, fish full lifecycle or invertebrate lifecycle studies) or use known sensitive life stages that are predictive of effects on the whole lifecycle.

Two-Generation Reproduction Toxicology Study[2]

In this multi-generational study, young, sexually mature animals (usually rats) are exposed for 10 weeks and mated. Once offspring are born, they are monitored until sexually mature. The cycle is repeated with offspring exposed and mated to produce another generation. Exposure is continuous throughout and as a result, covers the following sensitive biological processes and life stages:

  • Sexual development and release of gametes (sperm and eggs)
  • Mating and fertilization
  • Implantation of the conceptus (primitive embryo) in the uterus
  • Fetal growth and development (gestation/pregnancy)
  • Parturition (birth)
  • Lactation
  • Neonatal and juvenile development (pre- and post-weaning)
  • Growth and development to adulthood (including puberty)

Exposure includes high-dose levels – many orders of magnitude greater than actual human exposure levels. An additional feature of the study design is that the very young offspring receive exposures several fold greater than the parents, so particular emphasis and attention is paid to one of the most vulnerable life stages. Extensive assessments are made in these studies of the normal behavior, sexual performance, morphology and development of several generations of animals.

Prenatal Developmental Toxicity Studies[3]

In these studies, pregnant animals are exposed to high doses of pesticide active substances throughout pregnancy, after which exhaustive evaluations of in utero fetal development are conducted. These studies are conducted in two separate species, typically the rat and rabbit.

These two-generation, reproduction and prenatal developmental toxicity studies are considered a comprehensive evaluation for any potential effects during sensitive windows of exposure. Furthermore, the endpoints and biological processes (e.g., mating, implantation, pregnancy and neonatal development) evaluated in these studies are under extensive hormonal regulation, i.e., well suited to detect adverse effects resulting from interaction with the endocrine system.

There is a call by some for the introduction of a new test guideline in which animals are exposed throughout sensitive windows of exposure (including in utero) and then either further exposed until old age or simply monitored into old age without additional exposure.[4] However, the current testing regime detects reproductive, carcinogenic and ED effects and therefore, addresses all relevant adverse effect “types.” Furthermore, there is no evidence that the inclusion of in utero to old age studies would identify lower, more health protective levels for regulatory risk assessment.[5],[6] Therefore, from both hazard classification and risk assessment perspectives, the current testing paradigm for pesticides is appropriate.

Vulnerable Populations

These groups generally include pregnant or nursing women, the very young and very old. Concerns over early life stage sensitivity are well covered by the current regulatory testing paradigm. Effects in aging and old animals are also comprehensively assessed in chronic toxicity and carcinogenicity studies in rats and mice.

The U.S. Agency for Toxic Substances and Disease Registry of the U.S. Department of Health and Human Services lists general points on why these vulnerable groups may be more sensitive to chemical exposures.[7] These points and how they are addressed by current regulatory tests are summarized as follows:

Pregnant and Nursing Women

  • Exposures may affect the developing fetus: Potential for fetal effects is comprehensively covered by the current testing approach.
  • Potential for lactational transfer: This is assessed in the two-generation reproduction toxicity study.


  • Potential for higher exposure (e.g., by eating dirt, playing on the floor): Toxicology studies are conducted at a series of dose levels, including potential for increased exposure, and all considerably in excess of predicted human exposures.
  • Children have a more limited diet, so they may have more exposure to chemicals that are only in certain foods: In dietary toxicology studies, animals are administered the test item at high doses in the same diet every day.
  • Potential for developmental effects (e.g., during puberty): Effects are assessed in the two-generation reproduction toxicity study.

Older Adults

  • Potential for higher exposures (reduced potential for avoidance): Toxicology studies are conducted across a series of dose levels, including potential for increased exposure, and all considerably in excess of predicted human exposures.
  • Increased sensitivity to adverse effects owing to reduced potential to respond to exposure: The potential for increased sensitivity of geriatric animals is assessed in the chronic toxicity and carcinogenicity studies in rats and mice.

An extra level of protection is also provided for such groups during risk assessments. An assumption is made that populations will contain vulnerable, sensitive sub-populations so an additional 10-fold (intra-species variability) safety factor is applied to ensure these groups are adequately protected. This is in addition to the 10-fold (inter-species variability) safety factor applied when extrapolating results from animal toxicity studies to humans. Therefore, in total, a 100-fold safety factor is typically applied in risk assessments.

In the United States, there is a more stringent safety standard for most pesticides, particularly regarding the susceptibility of children. In addition to the safety factors described above, pesticide tolerance decisions utilize an additional 10-fold safety factor, as appropriate, in setting and reassessing tolerances.

For the environment (wildlife species), the protection goal is at the population, not individual, level. Therefore, adverse effects of any type are considered indicative of population-specific responses, namely growth, development and reproduction. All relevant ecotoxicological tests either address this directly by exposing all life stages (rat multi-generation, fish full lifecycle[8] or invertebrate lifecycle studies) or use known sensitive life stages that are predictive of effects on the whole lifecycle. Importantly, the highest tier ecotoxicological tests are all single or multi-generational in design so they consider all life stages by default.

In summary, the current regulatory testing and safety assessment of pesticide active substances addresses the potential for adverse effects from exposures during sensitive windows of exposure and to vulnerable groups. This applies to the detection all adverse health effects, including those involving the endocrine system.


[1] Sensitive windows of exposure: at conception and during fetal growth and development, pregnancy/in utero, development and growth throughout early life stages (neonatal and juvenile), and pubertal development and adolescence until early adulthood.

[2] United States Environmental Protection Agency.1996. OPPTS 870.3800 Reproduction and fertility effects [EPA 712–C–98–208].!documentDetail;D=EPA-HQ-OPPT-2009-0156-0018

[3] United States Environmental Protection Agency. 1998. OCSPPS 870.3700 Prenatal Developmental Toxicity Study [EPA 712–C–98–207].!documentDetail;D=EPA-HQ-OPPT-2009-0156-0017

[4] European Food Safety Authority Scientific Committee. 2013. Scientific Opinion on the hazard assessment of endocrine disruptors: Scientific criteria for identification of endocrine disruptors and appropriateness of existing test methods for assessing effects mediated by these substances on human health and the environment. EFSA Journal. 11(3):3132 (page 30).

[5] Gibson JP et al. 1967. Comparative chronic toxicity of three oral estrogens in rats. Toxicol Appl Pharmacol. 11: 489-510.

[6] Baggs RB et al. 1991. Carcinogenicity of diethylstilbestrol in the Wistar rat: Effect of postnatal oral contraceptive steroids. Cancer Res. 51: 3311-3315.

[7] Agency for Toxic Substances and Disease Registry, U.S. Department of Health and Human Services.

[8] Volz DC, Belanger S, Embry M, Padilla S, Sanderson H, Schirmer K, Schloz S, Villeneuve D. 2011. Adverse outcome pathways during early fish development: A conceptual framework for identification of chemical screening and prioritization strategies. Tox Sci. 123(2) 349-358.

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