TYPES OF TOXIC EFFECTS Because chemicals can affect organisms by different mechanisms

 Many factors play a potential role in toxicity. The dosage (or amount and at the molecular level, there are new ways to conduct toxicity
of exposure) is the most important factor. A well-known saying, "the testing.
dose makes the poison" speaks to this principle.  An emerging approach is to use Adverse Outcome Pathways
 Toxicity can result from adverse cellular, biochemical, or (AOPs), which evaluate changes in normal cellularpathways. AOPs
macromolecular changes. reflect the move away from high-dose studies in laboratory animals
 Many chemicals distribute in the body and often affect only specific for toxicity testing to in vitro methods that evaluate changes in
target organs. However, other chemicals can damage any cell or normal cellular pathways using human-relevant cells or tissues.
tissue that they contact. The target organs that are affected may vary  Other terms that describe changes resulting from the exposure of a
depending on dosage and route of exposure. For example, the living organism to a substance include mode ofaction (MoA) and
central nervous system may be the target organ for toxicity from a mechanism of action (MOA).
chemical afteracute exposure whereas the liver may be affected after a. Mode of action (MoA) (older term) — describes a functional or
chronic exposures anatomical change at the cellular level
 Chemicals can cause many types of toxicity by a variety of b. Mechanism of action (MOA) — describes such changes at the
mechanisms. Some act locally such as when direct exposuretriggers molecular level
skin or eye irritation, whereas other chemical cause systemic effects FACTORS INFLUENCING TOXICITY
in the body in sites remote from where the actual exposure occurred.  In some instances, individuals can have unpredictable reactions, or
 Toxicity can act directly affect subcellular components, such as cell idiosyncratic responses, to a drug or other substance.
receptors, or it can causeproblems at the cellular level, such as with  An idiosyncratic response is uncommon, and it is sometimes
exposures to caustic or corrosive substances. For example, impossible to understand whether it is the result of a genetic
chemicals might: predisposition or has some other cause such as the status of the
1. Themselves be toxic or require metabolism (chemical change immune system. It could result in an abnormally small or short, or
within the body) before they cause toxicity. abnormally large or long response to the drug or other substance.
2. Cause damage leading to fibrosis as the body attempts to repair Or, the response could be qualitatively different than what has been
the toxicity. observed in most other individuals.
3. Damage or disrupt an enzyme system or protein synthesis.  The toxicity of a substance usually depends on the following factors:
4. Produce reactive chemicals in cells. 1. Form and innate chemical activity
5. Cause changes in hormone signaling or other effects. 2. Dosage, especially dose-time relationship
6. Produce DNA damage or epigenetic changes. 3. Exposure route
 Some chemicals may also act indirectly by: 4. Species
a. Modifying an essential biochemical function. 5. Life stage, such as infant, young adult, or elderly adult
b. Interfering with nutrition. 6. Gender
c. Altering a physiological mechanism 7. Ability to be absorbed
DID YOU KNOW? 8. Metabolism
Mercury is a naturally occurring heavy metal. Methyl mercury, the most 9. Distribution within the body
common organic mercury compound, can be formed in water and soil by bacteria. 10. Excretion
It builds up in the tissues of fish. Exposure to high levels of mercury and mercury 11. Health of the individual, including organ function and pregnancy,
compounds can cause death or permanently damage the brain and kidneys. which involves physiological changes that could influence toxicity
In the late 1950s, people living around Japan's Minamata Bay developed 12. Nutritional status
symptoms of severe methylmercury poisoning, some of whom died. Children 13. Presence of other chemicals
exposed in utero were born with disabilities. Investigations showed that heavily 14. Circadian rhythms (the time of day a drug or other substance is
contaminated sludge from a factory had been released into the bay,
administered)
contaminating fish and shellfish. People who ate the fish and shellfish became ill.
The events led to a better understanding of industrial pollution and how heavy
metals can accumulate in systems.
In January 2013 the Minamata Convention on Mercury global treaty was
agreed to by an intergovernmentalcommittee. It seeks to protect human health
and the environment from the adverse effects of mercury
Factors Related to the Substance 4. Absorption
1. Form and Innate Chemical Activity  The ability to be absorbed is essential to systemic toxicity.
 The form of a substance may have a profound impact on its Some chemicals are readily absorbed and others are poorly
toxicity especially for metallic elements, also termed heavy absorbed. For example, nearly all alcohols are readily
metals absorbed when ingested, whereas there is virtually no
→ For example, the toxicity of mercury vapor differs absorption for most polymers.
greatly from methyl mercury.  The rates and extent of absorption may vary greatly
→ Another example is chromium. Cr3+ is relatively depending on the form of a chemical and the route of
nontoxic whereas Cr6+ causes skin or nasal exposure to it. For example:
corrosion and lung cancer. a. Ethanol is readily absorbed from the gastrointestinal
 The innate chemical activity of substances also varies tract but poorly absorbed through the skin.
greatly. Some can quickly damage cells causing immediate b. Organic mercury is readily absorbed from the
cell death. Others slowly interfere only with a cell's function. gastrointestinal tract; inorganic lead sulfate is not.
→ For example: Hydrogen cyanide binds to the Factors Related to the Organism
enzyme cytochrome oxidase resulting in cellular 1. Species
hypoxia and rapid death.  Toxic responses can vary substantially depending on the
→ Nicotine binds to cholinergic receptors in the central species. Most differences between species are attributable
nervous system (CNS) altering nerve conduction to differences in metabolism. Others may be due to
and inducing gradual onset of paralysis. anatomical or physiological differences. For example
2. Dosage a. Rats cannot vomit and expel toxicants before they are
 The dosage is the most important and critical factor in absorbed or cause severe irritation, whereas humans
determining if a substance will be an acute or a chronic and dogs are capable of vomiting.
toxicant. Virtually all chemicals can be acute toxicants if  Selective toxicity refers to species differences in toxicity
sufficiently large doses are administered. between two species simultaneously exposed. This is the
 Often the toxic mechanisms and target organs are different basis for the effectiveness of pesticides and drugs. For
for acute and chronic toxicity. Examples are: example:
Toxicant Acute Toxicity Chronic Toxic Effects a. An insecticide is lethal to insects but relatively nontoxic
Ethanol CNS depression Liver cirrhosis to animals.
Arsenic GI damage Skin/Liver cancer b. Antibiotics are selectively toxic to microorganisms while
virtually nontoxic to humans.
3. Exposure Route 2. Life Stage
 The way an individual comes in contact with a toxic  An individual's age or life stage may be important in
substance, or exposure route, is important in determining determining his or her response to toxicants. Some
toxicity. chemicals are more toxic to infants or the elderly than to
 Some chemicals may be highly toxic by one route but not by young adults. For example:
others. a. Parathion is more toxic to young animals.
 Two major reasons are differences in absorption and b. Nitrosamines are more carcinogenic to newborn or
distribution within the body. For example: young animals.
a. Ingested chemicals, when absorbed from the intestine, 3. Gender
distribute first to the liver and may be immediately  Gender can play a big role in influencing toxicity. Physiologic
detoxified. differences between men and women, including differences
b. Inhaled toxicants immediately enter the general blood in pharmacokinetics and pharmacodynamics, can affect drug
circulation and can distribute throughout the body prior activity.
to being detoxified by the liver.  In comparison with men, pharmacokinetics in women
 Different target organs often are affected by different routes generally can be impacted by their lower body weight, slower
of exposure. gastrointestinal motility, reduced intestinal enzymatic activity,
 and slower kidney function (glomerular filtration rate).  There is awareness that the gut microbiota can impact the
Delayed gastric emptying in women may result in a need for toxicity of drugs and other chemicals. For example, gut
them to extend the interval between eating and taking microbes can metabolize some environmental chemicals
medications that require absorption on an empty stomach. and bacteria-dependent metabolism of some chemicals can
Other physiologic differences between men and women also modulate their toxicity.
exist. Slower renal clearance in women, for example, may  Also, environmental chemicals can alter the composition
result in a need for dosage adjustment for drugs such as and/or the metabolic activity of the gastrointestinal bacteria,
digoxin that are excreted via the kidneys. thus contributing in a meaningful way to shape an
 In general, pharmacodynamic differences between women individual's microbiome.
and men include greater sensitivity to and enhanced 5. Distribution within the Body
effectiveness, in women, of some drugs, such as beta  The distribution of toxicants and toxic metabolites throughout
blockers, opioids, and some antipsychotics. the body ultimately determines the sites where toxicity
 Studies in animals also have identified gender-related occurs.
differences. For example:  A major determinant of whether a toxicant will damage cells
a. Male rats are 10 times more sensitive than females to is its lipid solubility. If a toxicant is lipid-soluble, it readily
liver damage from DDT. penetrates cell membranes.
b. Female rats are twice as sensitive to parathion as are  Many toxicants are stored in the body. Fat tissue, liver,
male rats. kidney, and bone are the most common storage sites.
4. Metabolism  Blood serves as the main avenue for distribution. Lymph
 Metabolism, also known as biotransformation, is the also distributes some materials
conversion of a chemical from one form to another by a 6. Excretion
biological organism.  The site and rate of excretion is another major factor
 Metabolism is a major factor in determining toxicity. The affecting the toxicity of a xenobiotic. The kidney is the
products of metabolism are known as metabolites. There are primary excretory organ, followed by the gastrointestinal
two types of metabolism: tract, and the lungs (for gases).
a. Detoxification  Xenobiotics may also be excreted in sweat, tears, and milk.
→ In detoxification, a xenobiotic is converted to a  A large volume of blood serum is filtered through the kidney.
less toxic form. This is a natural defense Lipid-soluble toxicants are reabsorbed and concentrated in
mechanism of the organism. Generally, kidney cells.
detoxification converts lipid-soluble compounds  Impaired kidney function causes slower elimination of
to polar compounds. toxicants and increases their toxic potential.
b. Bioactivation 7. Health Status
→ In bioactivation, a xenobiotic may be converted  The health of an individual or organism can play a major role
to more reactive or toxic forms. in determining the levels and types of potential toxicity. For
→ Cytochrome P-450 (CYP450) is an example of example, an individual may have pre-existing kidney or liver
an enzyme pathway used to metabolize drugs. disease.
→ In the elderly, CYP450 metabolism of drugs
 Certain conditions, such as pregnancy, also are associated
such as phenytoin and carbamazepine may be
with physiological changes in kidney function that could
decreased. Therefore, the effect of those drugs
influence toxicity.
may be less pronounced.
8. Nutritional Status
→ CYP450 metabolism also can be inhibited by
 Diet (nutritional status) can be a major factor in determining
many drugs.
who does or does not develop toxicity. For example:
→ Risk of toxicity may be increased if a CYP450
a. Consumption of fish that have absorbed mercury from
enzyme-inhibiting drug is given with one that
contaminated water can result in mercury toxicity; an
depends on that pathway for metabolism.
antagonist for mercury toxicity is the nutrient selenium.
 b. Some vegetables can accumulate cadmium from b. Many people die each year from inhaling carbon
contaminated soil; an antagonist for cadmium toxicity is monoxide from faulty heaters.
the nutrient zinc. 2. Subchronic Toxicity
c. Grapefruit contains a substance that inhibits the P450  Subchronic toxicity results from repeated exposure for
drug detoxification pathway, making some drugs more several weeks or months.
toxic.  This is a common human exposure pattern for some
9. Circadian Rhythms pharmaceuticals and environmental agents.
 Circadian rhythms can play a role in toxicity. For example,  For example:
rats administered an immunosuppressive drug had severe a. Ingestion of warfarin (Coumadin®) tablets (blood
toxicity in their intestines 7 hours after light onset compared thinners) for several weeks as a treatment for venous
to controls and to other times in the day. The rats had thrombosis can cause internal bleeding.
changes in their digestive enzyme activity and other b. Workplace exposure to lead over a period of several
physiological indicators at this dosing time weeks can result in anemia.
Other Factors 3. Chronic Toxicity
 The presence of other chemicals, at the same time, earlier, or later  Chronic toxicity represents cumulative damage to specific
may: organ systems and takes many months or years to become
a. Decrease toxicity (antagonism) a recognizable clinical disease.
b. Add to toxicity (additivity)  Damage due to subclinical individual exposures may go
c. Increase toxicity (synergism or potentiation) unnoticed.
 For example:  With repeated exposures or long-term continual exposure,
a. Antidotes used to counteract the effects of poisons function the damage from this type of exposure slowly builds up
through antagonism (atropine counteracts poisoning by (cumulative damage) until the damage exceeds the
organophosphate insecticides). threshold for chronic toxicity.
b. Alcohol may enhance the effect of many antihistamines and  Ultimately, the damage becomes so severe that the organ
sedatives. can no longer function normally and a variety of chronic toxic
c. A synergistic interaction between the antioxidant butylated effects may result.
hydroxytoluene (BHT) and a certain concentration of oxygen  Chronic toxic effects include:
results in lung damage in the form of interstitial pulmonary a. Cirrhosis in alcoholics who have ingested ethanol for
fibrosis. several years.
SYSTEMIC TOXIC EFFECTS b. Chronic kidney disease in workmen with several years of
 Toxic effects are generally categorized according to the site of the exposure to lead.
toxic effect. In some cases, the effect may occur at only one site. c. Chronic bronchitis in long-term cigarette smokers.
This site is termed the specific target organ. d. Pulmonary fibrosis in coal miners (black lung disease).
 In other cases, toxic effects may occur at multiple sites. This is 4. Carcinogenicity
known as systemic toxicity.
 Carcinogenicity is a complex multistage process of abnormal
Types of Systemic Toxic Effects
cell growth and differentiation that can lead to cancer.
1. Acute Toxicity
 The two stages of carcinogenicity are:
 Acute toxicity occurs almost immediately
a. Initiation — a normal cell undergoes irreversible
(seconds/minutes/hours/days) after an exposure.
changes.
 An acute exposure is usually a single dose or a series of b. Promotion — initiated cells are stimulated to progress to
doses received within a 24-hour period. cancer.
 Death can be a major concern in cases of acute exposures.  Chemicals can act as initiators or promoters.
 For example:  The initial transformation that causes normal cells to
a. In 1989, 5,000 people died and 30,000 were undergo irreversible changes results from the mutation of the
permanently disabled due to exposure to methyl cellular genes that control normal cell functions. The
isocyanate from an industrial accident in India. mutation may lead to abnormal cell growth. It may involve a
 loss of suppresser genes that usually restrict abnormal cell  If the mutation occurs in a somatic cell, it can cause altered
growth. cell growth (for example, cancer) or cell death (for example,
 Many other factors are involved, such as growth factors, teratogenesis) in the exposed person.
immune suppression, and hormones. ORGAN-SPECIFIC TOXIC EFFECTS
 A tumor (neoplasm) is simply an uncontrolled growth of cells:  Toxic effects that pertain to specific organs and organ systems
a. Benign tumors grow at the site of origin; do not invade include:
adjacent tissues or metastasize; and generally are 1. Blood and Cardiovascular/Cardiac Toxicity
treatable.  Blood and Cardiovascular/Cardiac Toxicity results from
b. Malignant tumors (cancer) invade adjacent tissues or xenobiotics acting directly on cells in circulating blood,
migrate to distant sites (metastasis). They are more bone marrow, and the heart. Examples of blood and
difficult to treat and often cause death. cardiovascular/cardiac toxicity are:
5. Developmental Toxicity a. Hypoxia due to carbon monoxide binding of
 Developmental toxicity pertains to adverse toxic effects to hemoglobin preventing transport of oxygen.
the developing embryo or fetus. It can result from toxicant b. Decrease in circulating leukocytes due to
exposure to either parent before conception or to the mother chloramphenicol damage to bone marrow cells.
and her developing embryo or fetus. c. Leukemia due to benzene damage of bone marrow
 The three basic types of developmental toxicity are: cells.
a. Embryolethality — failure to conceive, spontaneous d. Arteriosclerosis due to cholesterol accumulation in
abortion, or stillbirth. arteries and veins.
b. Embryotoxicity — growth retardation or delayed growth e. Death of normal cells in and around the heart as a
of specific organ systems. result of exposure to drugs used to treat cancer.
c. Teratogenicity — irreversible conditions that leave 2. Dermal Toxicity
permanent birth defects in live offspring, such as cleft  Dermal Toxicity can occur when a toxicant comes into
palette or missing limbs. direct contact with the skin or is distributed to it
 Chemicals cause developmental toxicity in two ways: internally.
a. They act directly on cells of the embryo, causing cell  Effects range from mild irritation to severe changes,
death or cell damage, leading to abnormal organ such as irreversible damage, hypersensitivity, and skin
development. cancer.
b. They induce a mutation in a parent's germ cell, which is  Examples of dermal toxicity include:
transmitted to the fertilized ovum. Some mutated a. Dermal irritation from skin exposure to gasoline.
fertilized ova develop into abnormal embryos. b. Dermal corrosion from skin exposure to sodium
6. Genetic Toxicity hydroxide (lye).
 Genetic toxicity results from damage to DNA and altered c. Dermal itching, irritation, and sometimes painful rash
genetic expression. This process is known as mutagenesis. from poison ivy, caused by urushiol.
The genetic change is referred to as a mutation and the d. Skin cancer due to ingestion of arsenic or skin
agent causing the change is called a mutagen. exposure to UV light.
 There are three types of genetic changes: 3. Epigenetic Alterations
a. Gene mutation — change in DNA sequence within a  Epigenetics is an emerging area in toxicology.
gene.  In the field of genetics, epigenetics involves studying
b. Chromosome aberration — changes in the chromosome how external or environmental factors can switch genes
structure. on and off and change the programming of cells.
c. Aneuploidy or polyploidy — increase or decrease in  More specifically, epigenetics refers to stable changes in
number of chromosomes. the programming of gene expression which can alter the
 If the mutation occurs in a germ cell, the effect is heritable. phenotype without changing the DNA sequence
This means there is no effect on the exposed person; rather, (genotype).
the effect is passed on to future generations.
  Epigenetic modifications include DNA methylation, 5. Hepatotoxicity
covalent modifications of histone tails, and regulation by  Hepatotoxicity is toxicity to the liver, bile duct, and gall
non-coding RNAs, among others. bladder. Because of its extensive blood supply and
 Toxicants are examples of factors that can alter genetic significant role in metabolism, the liver is particularly
programming. susceptible to xenobiotics Thus, it is exposed to high
 In the past, toxicology studies have assessed toxicity doses of the toxicant or its toxic metabolites.
without measuring its impact at the level where gene  The primary forms of hepatotoxicity are:
expression occurs. Exogenous agents could cause long- a. Steatosis — lipid accumulation in the hepatocytes.
term toxicity that continues after the initial exposure has b. Chemical hepatitis — inflammation of the liver.
disappeared, and such toxicities remain undetected by c. Hepatic necrosis — death of the hepatocytes.
current screening methods. Thus, a current challenge in d. Intrahepatic cholestasis — backup of bile salts into
toxicology is to develop screening methods that would the liver cells.
detect epigenetic alterations caused by toxicants. e. Hepatic cancer — cancer of the liver.
 Research is being done to assess epigenetic changes f. Cirrhosis — chronic fibrosis, often due to alcohol.
caused by toxicants. For example, the National Institutes g. Hypersensitivity — immune reaction resulting in
of Health (NIH) National Institute of Environmental hepatic necrosis.
Health Sciences (NIEHS) Environmental Epigenetics 6. Immunotoxicity
program provides funding for a variety of research  Immunotoxicity is toxicity of the immune system. It can
projects that use state-of-the-art technologies to analyze take several forms:
epigenetic changes caused by environmental a. Hypersensitivity (allergy and autoimmunity)
exposures. NIEHS-supported researchers use animals, b. Immunodeficiency\
cell cultures, and human tissue samples to pinpoint how c. Uncontrolled proliferation (leukemia and lymphoma)
epigenetic changes can lead to harmful health effects  The normal function of the immune system is to
and can potentially be passed down to the next recognize and defend against foreign invaders. This is
generation. accomplished by production of cells that engulf and
4. Eye Toxicity destroy the invaders or by antibodies that inactivate
 Eye Toxicity results from direct contact with or internal foreign material.
distribution to the eye.  Examples include:
 Because the cornea and conjunctiva are directly a. Contact dermatitis due to exposure to poison ivy.
exposed to toxicants, conjunctivitis and corneal erosion b. Systemic lupus erythematosus ("lupus") in workers
may be observed following occupational exposure to exposed to hydrazine.
chemicals. c. Immunosuppression by cocaine.
 Many household items can cause conjunctivitis. d. Leukemia induced by benzene.
Chemicals in the circulatory system can distribute to the 7. Nephrotoxicity
eye and cause corneal opacity, cataracts, and retinal  The kidney is highly susceptible to toxicants because a
and optic nerve damage. high volume of blood flows through the organ and it
 For example: filters large amounts of toxins which can concentrate in
a. Acids and strong alkalis may cause severe corneal the kidney tubules.
corrosion.  Nephrotoxicity is toxicity to the kidneys. It can result in
b. Corticosteroids may cause cataracts. systemic toxicity causing:
c. Methanol (wood alcohol) may damage the optic a. Decreased ability to excrete body wastes.
nerve. b. Inability to maintain body fluid and electrolyte
balance.
c. Decreased synthesis of essential hormones (for
example, erythropoietin, which increases the rate of
blood cell production).
 8. Neurotoxicity c. In which a first agent modifies the cell and tissue response to a
 Neurotoxicity represents toxicant damage to cells of the second agent.
central nervous system (brain and spinal cord) and the  Interactions may occur by:
peripheral nervous system (nerves outside the CNS). a. Simultaneous exposure to two or more agents.
 The primary types of neurotoxicity are: b. Exposure to two or more agents at different times.
a. Neuronopathies (neuron injury) Sources of Interactions
b. Axonopathies (axon injury)  Humans are normally exposed to many chemicals at one time. For
c. Demyelination (loss of axon insulation) example, the use of consumer products, medical treatments, and
d. Interference with neurotransmission exposures from the diet and environment (such as from soil, air, and
9. Reproductive Toxicity water) can consist of exposures to hundreds, if not thousands, of
 Reproductive Toxicity involves toxicant damage to either chemicals.
the male or female reproductive system.  Other examples include:
 Toxic effects may cause: a. Hospital patients receive an average of six drugs daily.
a. Decreased libido and impotence. b. Consumers may use five or more consumer products before
b. Infertility. breakfast (for example, soap, shampoo, conditioner, toothpaste,
c. Interrupted pregnancy (abortion, fetal death, or and deodorant).
premature delivery). c. Home influenza treatment consists of aspirin, antihistamines,
d. Infant death or childhood morbidity. and cough syrup taken simultaneously.
e. Altered sex ratio and multiple births. d. Drinking water may contain small amounts of pesticides, heavy
f. Chromosome abnormalities and birth defects. metals, solvents, and other organic chemicals.
g. Childhood cancer. e. Air often contains mixtures of hundreds of chemicals such as
10. Respiratory Toxicity automobile exhaust and cigarette smoke.
 Respiratory Toxicity relates to effects on the upper f. Gasoline vapor at service stations is a mixture of 40-50
respiratory system (nose, pharynx, larynx, and trachea) chemicals.
and the lower respiratory system (bronchi, bronchioles,  Toxicology studies and human health risk assessments have
and lung alveoli). traditionally focused primarily on a single chemical. However, as
 The primary types of respiratory toxicity are: noted above, people are exposed to many chemicals every day.
a. Pulmonary irritation They are also exposed to non-chemical stressors every day and
b. Asthma/bronchitis throughout a lifetime.
c. Reactive airway disease  In addition, non-chemical stressors include infectious agents, diet,
d. Emphysema and psychosocial stress, all of which have potential roles in
e. Allergic alveolitis contributing to the health effects associated with chemical
f. Fibrotic lung disease exposures.
g. Pneumoconiosis Approaches for Assessing Interactions
h. Lung cancer  Development of methods to assess the health effects associated
INTERACTIONS with complex exposures is underway at various organizations.
 The presence of other chemicals, at the same time, earlier, or later  Non-animal tools and approaches are demonstrating high potential
may: for use in assessing combined effects of chemicals on humans and
a. Decrease toxicity (antagonism). the environment. These tools and approaches may help uncover
b. Add to toxicity (additivity). information about new mixture components or entire mixtures, which
c. Increase toxicity (synergism or potentiation) of some chemicals. can promote understanding of the underlying mechanisms of their
 For example, interactions between two or more toxic agents can combined effects. The strategies for assessing interactions rely less
produce lung damage by interactions: on in vivo testing and more on non-animal studies and computational
a. Between chemicals. tools and incorporate emerging approaches such as:
b. Between chemicals and receptors. a. The adverse outcome pathway (AOP) concept.
b. In vitro methods.
 c. “Omics” techniques.
d. In silico approaches such as quantitative structure activity
relationships (QSARs).
e. Read-across.
f. Toxicokinetic modeling.
g. Integrated approaches to testing and assessment (IATA).
 The goals include the ability to development more effective and
comprehensive regulatory assessments while reducing the reliance
on animal testing