Developmental toxicity is any developmental malformation that is caused by the toxicity of a chemical or pathogen. It is the structural or functional alteration, reversible or irreversible, which interferes with homeostasis, normal growth, differentiation, development or behavior. Developmental toxicity is caused by environmental factors, things like drugs, alcohol, diet, toxic chemicals, and physical factors that alter the developmental process.
More factors causing developmental toxicity are radiation, infections (e.g. rubella), maternal metabolic imbalances (e.g. alcoholism, diabetes, folic acid deficiency), drugs (e.g. anticancer drugs, tetracyclines, many hormones, thalidomide), and toxic environmental chemicals (e.g. mercury, lead, dioxins, PBDEs, HBCD, tobacco smoke).In addition, it is the study of adverse effects on the development of the organism that can result from exposure to toxic agents before conception, during fetal development, or even following birth.
Certain pathogens are also included since the toxins they secrete are known to cause adverse effects on the development of the organism when the mother or fetus is infected. In the past there was a field of study that looked at primarily structural congenital abnormalities, which is another way of saying physical deformities. This field of study has widely been replaced by what is known now as teratology to enable inclusion of a more diverse spectrum of congenital disorders. The substances that cause developmental toxicity from embryonic stage to birth are called teratogens. The effect of the developmental toxicants depends on the type of substance, dose, duration, and time of the exposure. The first few weeks of embryogenesis in humans is more susceptible to these agents.
The embryogenesis is the most crucial time for the action of any teratogenic substances to result in birth defects. Once fertilization has taken place, the toxicants in the environment can pass through the mother to the developing embryo or fetus across the placental barrier. The fetus is at greatest risk during the first 14th to 60th day of the pregnancy when the major organs are being formed. However, depending on the type of toxicant and amount of exposure, a fetus can be exposed to toxicants at any time during pregnancy, but have different effects. For example, exposure to a particular toxicant at one time in the pregnancy may result in organ damage and at another time in the pregnancy could cause death of the fetus and miscarriage.
There are a number of chemicals, biological agents (such as bacteria and viruses), and physical agents (such as radiation) used in a variety of workplaces that are known to cause developmental disorders. Developmental disorders can include a wide range of physical abnormalities, such as bone or organ deformities, or behavioral and learning problems, such as an intellectual disability. Exposures to some chemicals during pregnancy can lead to the development of cancer later in life, called transgenerational carcinogens. Exposure to toxicants during the second and third trimesters of a pregnancy can lead to slow fetal growth and result in low birth weight.
History Toxicology research is the study of the adverse effects of chemicals or physical agents on living organisms. The scientific study of poisons dates to Ancient Egypt, China, and Greece. Ebers Papyrus from 1500 BCE contains information on many poisons including hemlock. Shen Hung (2605 BCE, China) tested hundreds of herbs and wrote the first Pharmacopoeia. Mathieu Orfila, a 19th-century Spanish physician and scientist, is a founder of modern toxicology that autopsied poison victims to evaluate target organ specific effects (liver, kidney, GI tract, brain, etc.).
Researchers have been able to ascertain toxicity associated with abnormal development with new breakthrough in developmental biology. Recognition of the developmental toxic effects of various molecules is a recent development. Unfortunately, the damage caused by these toxicants can be very subtle, and even when identified it can be difficult to persuade lawmakers to enact change.
Terato means monster in Greek. Until the 18th century, the preformism theory was accepted by which abnormal growth was considered as deformations. The 19th century saw developmental in descriptive embryology where abnormalities were now considered as malformations or errors during a developmental process giving rise to the concept of teratogenesis. By the 20th century, the concept of epigenesis the interaction between a genetic program and environment was established and in the second half of the 20th century researchers had evidence that environmental factors can cause malformations and even trans-generational effects.
This type of specific research that looks for malformations in fetal development is called Developmental and Reproductive Toxicology (DART).
Testing and risk assessment Testing for developmental toxicant is done in different stages: Fertilization to implantation - Fertilization followed by increase in cell number, cleavage and cavitation to form the blastocyst which gets implanted. Toxicant exposure at this stage usually prevents implantation and results in death. e.g. DDT, nicotine Implantation to gastrulation - The three germ layers are formed and the cells start migrating out to initiate organogenesis. This is most sensitive stage for alcohol toxicity. Organogenesis - It is the formation of limbs, organs, nervous system, urinary and genital systems by the process of cell differentiation, migration and cell interactions from the 3rd to 8th week of human gestation. e.g. DES Morphogenesis - Includes the stages of growth and physiological maturation from week 8 until birth. Teratogenic effects results in deformations and rather than malformations in the fetus. Post Natal to puberty - Environmental toxicant exposures.
DART (Developmental and Reproductive Toxicology) DART is the specific research of looking for malformations from the toxicity of chemicals, medications, pesticides, dietary supplements, etc. The National Toxicology Program (NTP) has been conducting DART research for chemicals that have not been FDA approved or undergone the appropriate research for human offspring.
The research is conducted by using pregnant animals and exposing them to a certain chemical, medication, drug, pesticide, etc. throughout their pregnancy and then complete teratology on the fetuses to look for malformations. These malformations can be anything from a tissue malformation to a skeletal malformation. They can also allow the animal to deliver the offspring to look for malformations in growing animals. These malformations can be anything from behaviors, intellect, sexual maturity such as testicular development, vaginal opening, and the ability to reproduce.
Because of the complexity of the embryo-fetal development, including the maternal-fetal interactions during gestation, it is important to understand the mechanism of toxicity and test the toxic effect in up to two species before confirming the substance to be a developmental toxicant. Embryo have different critical periods for the organ formation from day 15 to day 60 and hence the susceptibility to toxicant injury is directly related to the period of development.
Risk Assessment Guidelines Risk Assessment is defined as a process to make a scientifically sound judgement to identify the potential toxicity cause in human by a substance.US EPA (United States Environmental Protection Agency). 1991. Guidelines for developmental toxicity risk assessment. EPA/600/FR-91/001. Federal Register December 5, 1991. 56234:63798–826. As defined by National Research Council, Risk assessment process is composed of hazard identification, dose response, exposure assessment, and risk characterization.
Hazard Identification There are multiple possible endpoints to developmental toxicity that can be used to identify the manifestations of developmental toxicity with manifestations of developmental toxicity can be, but not limited to, death, maternal toxicity, and altered growth. The manifestation of developmental toxicity can be measured in laboratory animals in a research study using protocols that is provided by developmental toxicity guidelines or other study's protocol; these manifestations can be found within human study as well.
In laboratory animal studies, the substance being studied is commonly introduced to pregnant animals appropriate to the study in different dosage during major organogenesis via oral route of exposure and maternal response to the substance was gather as well as other data such as weight, age, and health status to reduces bias. Route of exposure, parentals exposure, and other variables can be manipulated depending on the studies. The data are then used to interpret the endpoints of the manifestations above such as the endpoint of maternal toxicity can includes fertility index, mortality, gestation length, and body weight change, and endpoint of developmental toxicity (altered growth) can include stillbirth rate, survival rate, malformation rate, and resorption rates.
Guidelines for laboratory animal are, but not limited to, several similar aspects of the study to previous developmental toxicity, replicated study provides confidence in the conclusion, critical periods for disruption range between prenatal to postnatal sexual maturation, and postnatal data should also considered exposure to maternal interactions.
In human studies, epidemiology studies and case studies are used to collect data. General design consideration of human studies includes the ability of the study to detect the true effects, potential bias in data collection due to other people not participating in data collection either by choice or not, other risk factors were taken into consideration to reduce bias, and statistical factors that can lead to overestimation or underestimation of the true effects.
Dose Response Human and animal studies are both used to determine the dose-response relationship; however, due to limited amount of human data, animal studies are most commonly used to determine the dose-response relationship of developmental toxicity. The dosage the developmental toxicity agent is usually near maternally toxic range. It is needed to be note that dose-response relationship may not be observed clearly for some endpoints.
The use of NOAEL and LOAEL are to evaluate the dose-response relationship for developmental toxicity with NOAEL identifies the highest dose where there are no significant adverse effects are observed while LOAEL identifies the lowest dose where there are significant adverse effects are observed. However, due to limitation from both NOAEL and LOAEL such as only focusing on one experimental dose and not incorporate of the slopes, Benchmark dose is developed to identify the incidence level within or near the range.
Certain principles are used to determined NOAEL, LOAEL, and Benchmark dose. For one, an assumption of a single exposure at critical time will produce an adverse side effect. Second is that NOAEL, LOAEL, and Benchmark dose for developmental, maternal, and/or adult toxicity for pregnant female, lactating female, or paternal male (if applicable) are compared to other adult toxicity such as nonpregnant female or adult males.
Exposure Assessment Exposure Assessment describes the magnitude, route of exposure, duration, and frequency of the exposure to the agents. There are some unique considerations for developmental toxicity. First, the exposure from placental transfer, breast milk or both parents being exposed to the agent before conception needs to be taken into consideration. Second, the duration and periods of exposure are measured in developmental stages such as first, second, or third trimester. Finally, exposure through environmental factor also needs to be taken into consideration.
Risk Characterization