Final Flashcards
1
Q
What is developmental toxicology?
A
Developmental toxicology refers to the adverse effects of xenobiotics (foreign substances) that occur between conception and puberty. An example is diethylstilbestrol.
2
Q
What is teratogenesis?
A
Teratogenesis refers to the adverse effects of xenobiotics that occur between conception and birth. An example is thalidomide.
3
Q
What are the three main categories of causes of developmental toxicity?
A
Known genetic factors (~25%)
Known environmental factors (~10-15%)
Unknown multifactorial causes (~60%)
4
Q
What are the most common known genetic factors causing developmental toxicity?
A
The most common known genetic factors are chromosomal abnormalities (e.g., Down’s Syndrome) and single-gene defects.
5
Q
What are some known environmental factors contributing to developmental toxicity?
A
Infections (bacteria, viruses; ~3%)
Maternal factors (e.g., disease, nutrition; ~4%)
Environmental toxicants and drugs (xenobiotics), referred to as teratogens (~5%)
Ionizing radiation and other physical factors (~1-2%)
6
Q
What constitutes unknown multifactorial causes of developmental toxicity?
A
Includes genetic-environmental interactions and epigenetics, particularly during gametogenesis in parents and early development between the zygote and blastocyst stages (imprinting).
7
Q
According to Wilson’s General Principles of Teratology, how does susceptibility to teratogenesis depend on genotype?
A
Susceptibility to teratogenesis depends on the genotype of the conceptus and how it interacts with adverse environmental factors.
8
Q
How does the developmental stage at the time of exposure affect susceptibility to teratogenesis?
A
Susceptibility to teratogenesis varies with the developmental stage at the time of exposure to an adverse influence.
9
Q
How do teratogenic agents act on developing cells and tissues?
A
Teratogenic agents act in specific ways (mechanisms) on developing cells and tissues to initiate sequences of abnormal developmental events (pathogenesis).
10
Q
What determines the access of adverse influences to developing tissues?
A
The access of adverse influences to developing tissues depends on the nature of the influence (agent).
11
Q
What are the four manifestations of deviant development according to Wilson’s principles?
A
The four manifestations are death, malformation, growth retardation, and functional deficit.
12
Q
How does the frequency and degree of deviant development change with dosage?
A
The manifestations of deviant development increase in frequency and degree as dosage increases, from no effect to a totally lethal level.
13
Q
What are the major considerations for susceptibility to teratogenesis according to Principles I & II?
A
The genotype of the embryo/fetus (intrinsic factors) and the environment (extrinsic factors, including maternal factors and external environmental factors).
14
Q
During which developmental stage is sensitivity to teratogens the highest?
A
The most sensitive period is organogenesis.
15
Q
What is the typical sensitivity to teratogen exposure during early development (fertilization to implantation)?
A
There is usually lower sensitivity to teratogen exposure during early development.
16
Q
What key events occur during the gastrulation stage of early development?
A
The formation of the ectoderm, mesoderm, and endoderm occurs, followed by the migration of these cellular germ layers. Teratogens can cause malformations of the eye, brain, and face during this period.
17
Q
What makes organogenesis a highly sensitive developmental stage?
A
Organogenesis is highly sensitive due to significant cell division, differentiation, migration, and remodeling during organ and tissue development.
18
Q
What are the key developmental events during organogenesis that coincide with peaks of sensitivity?
A
Key developmental events include the formation and development of organs and tissues.
19
Q
Provide an example of a teratogen that affects organogenesis and its effects.
A
Thalidomide is a teratogen that can cause amelia (missing limbs) and phocomelia (shortened limbs) when exposure occurs during the specific period of 20-36 days after fertilization in humans.
20
Q
What are the main focus areas during the fetal period in terms of developmental processes?
A
The fetal period involves histogenesis and functional maturation of organs and tissues.
21
Q
How do teratogenic effects differ in the fetal period compared to the embryonic period?
A
In the fetal period, teratogenic effects are more functional in nature (e.g., affecting the CNS, behavior, immune system, and reproductive system), whereas in the embryonic period, structural/morphological effects are more prevalent.
22
Q
What is a common effect of teratogens during the fetal period?
A
Reduced growth (birth weight) is a common effect of teratogens during the fetal period.
23
Q
What is an example of species differences in teratogenic effects?
A
Thalidomide causes phocomelia/amelia in humans but not in rats or mice.
24
Q
What are the implications of species differences for risk assessment when testing animals for teratogenicity?
A
Species differences must be considered to accurately assess the risk of teratogens, as responses can vary significantly between species.
25
How does the appearance of smooth endoplasmic reticulum (SER) in the liver differ between humans and rodents during gestation?
In humans, SER appears early in gestation (1st trimester, days 40-60), whereas in mice and rats, SER appears just before birth.
26
What does the early appearance of SER in humans imply about fetal detoxification of xenobiotics compared to rodents?
The early appearance of SER in humans implies that the human fetus can detoxify xenobiotics early in development compared to rodents.
27
How can bioactivation of xenobiotics by CYP affect teratogenicity in humans?
If a xenobiotic is bioactivated by CYP, it can be more teratogenic in humans during the sensitive period of organogenesis.
28
What is the general sequence leading to developmental toxicity from teratogenic agents?
Teratogenic agents act in specific ways (mechanisms) on developing cells and tissues to initiate sequences of abnormal developmental events (pathogenesis), leading to developmental toxicity.
29
Here are some general teratogenic mechanisms:
Gene ______ and chromosomal _______
Altered ______ or _______
Altered ______ _____ integrity or function
Reduced precursors or substrates for ________
mutations, abnormalities
mitosis, apoptosis
nucleic acid
metabolism
30
Here are some more general teratogenic mechanisms:
Reduced _______ sources
_______ imbalances (e.g., edema)
Altered cellular ________
_______ inhibition
energy
Osmotic
membranes
Enzyme
31
How can altered cell death contribute to teratogenesis?
Altered cell death, including both increased or decreased apoptosis, can be a major effect of teratogens, disrupting the delicate balance between cellular mitosis, apoptosis, and differentiation in the embryo.
32
What are some pathogenic responses to teratogens (3)?
Altered cell-cell interactions
Reduced biosynthesis of endogenous compounds
Inhibition of morphogenesis (which dictates the shape of organs, tissues, and organisms)
33
What are the three primary sources of teratogenesis?
Direct effects on the embryo/fetus
Placental factors (nutrition, gas exchange, waste removal, hormone production, biotransformation, and target organ for xenobiotics)
Maternal factors (genetics, disease, nutrition, physiological and psychological stress, ethanol or tobacco smoke consumption)
34
How do lipophilic xenobiotics cross the placenta?
Lipophilic xenobiotics follow the concentration gradient and passively diffuse across the placenta from maternal to fetal circulation. For certain xenobiotics, facilitated and active transport mechanisms can also play a role.
35
How does pregnancy affect maternal cardiac output and plasma proteins, and what are the implications?
During pregnancy, maternal cardiac output is 50% greater and plasma proteins decrease. This affects the volume of distribution and uptake of xenobiotics by the fetus.
36
What types of biotransformation enzymes does the placenta express?
The placenta expresses Phase 1 and Phase 2 biotransformation enzymes.
37
By when does the fetus express Phase 1 and Phase 2 biotransformation enzymes, and to what extent compared to the mother?
The fetus expresses Phase 1 and Phase 2 biotransformation enzymes by the end of the 1st trimester, albeit to a reduced extent (20-40%) compared to the mother.
38
How does the pH difference between fetal and maternal blood affect the transfer of xenobiotics?
Fetal blood has a slightly lower pH than maternal blood, which has implications for the transfer of xenobiotics that are weak acids or bases.
39
What are the common effects of teratogens during the early embryonic stage?
The common effect during the early embryonic stage is death.
40
When are malformations most likely to occur due to teratogen exposure?
Malformations are most likely to occur during the 1st trimester (organogenesis).
41
During which trimesters is growth retardation a common teratogenic effect?
Growth retardation is a common effect during the 2nd and especially the 3rd trimesters.
42
Which systems are primarily affected by functional deficits due to teratogen exposure in the 2nd and 3rd trimesters?
The central nervous system (CNS), reproductive system, and immune system are primarily affected by functional deficits.
43
What factors influence the frequency and severity of teratogenic effects?
The frequency and severity of teratogenic effects are proportional to the timing of exposure (Principle II), dose, and duration of exposure.
44
Why is teratogenicity considered a "threshold phenomenon"?
Because no effect occurs below a certain dose due to maternal and fetal defense/repair mechanisms and the high growth potential of the embryo/fetus.
45
How does the dose of a xenobiotic relate to the degree of teratogenic effects?
Lower doses of a xenobiotic cause growth retardation and more subtle functional deficits, while higher doses cause lethality.
46
What was thalidomide prescribed for between 1957-1961, and what were its adverse effects?
Thalidomide was prescribed to pregnant women to prevent morning sickness. It caused structural defects in over 10,000 children, leading to amelia (missing limbs) and phocomelia (shortened limbs), among other organ and tissue defects.
47
How did the thalidomide disaster impact drug testing for toxicities?
The thalidomide disaster completely changed the way humans test drugs and other chemicals for toxicities such as teratogenesis, forming the basis for Wilson’s 6 principles of teratology in 1959.
48
What is diethylstilbestrol (DES), and what were its long-term effects?
DES is a synthetic non-steroidal estrogen used to prevent miscarriage. It was linked to a rare form of vaginal cancer (clear cell adenocarcinoma) in daughters ("DES daughters") and other reproductive tract effects in sons and daughters. Recent studies show transgenerational epigenetic effects in 3rd generation offspring ("DES granddaughters").
49
What is Fetal Alcohol Syndrome (FAS) and how has our understanding of it evolved over time?
FAS is a developmental disorder recognized formally in 1971, caused by ethanol consumption during pregnancy. Initially focused on structural effects and growth retardation, it is now understood as part of Fetal Alcohol Spectrum Disorders (FASD) with profound effects on cognitive, behavioral, and motor functions.
50
What are the developmental toxicity outcomes of smoking during pregnancy?
Smoking during pregnancy can cause abortion, perinatal mortality, lower birth weight, sudden infant death syndrome, and brain/behavior disorders. Nicotine is a well-known neuroteratogen, and tobacco smoke contains hundreds of other toxic xenobiotics.
51
What are the effects of drug abuse (cocaine, methamphetamine, heroin, THC) during pregnancy?
Drug abuse during pregnancy causes a spectrum of disorders affecting the brain and behavior. Recent studies indicate that THC (psychoactive ingredient in cannabis) can cause CNS-associated deficits in offspring.
52
How can retinoids and antiepileptic drugs (AEDs) affect pregnancy?
Retinoids: Vitamin A (retinol) used in acne treatments like Accutane can cause a broad range of structural and functional deficits during the 1st trimester.
AEDs: Drugs like valproic acid, phenytoin, and carbamazepine can increase the risk of embryo/fetal mortality and deficits when administered during pregnancy.
53
What are Endocrine Disrupting Chemicals (EDCs), and what concerns do they raise?
EDCs are xenobiotics that interfere with hormone synthesis, secretion, transport, binding, action, or elimination, affecting homeostasis, reproduction, development, and behavior. Prenatal and childhood exposure to EDCs may lead to abnormalities in sexuality, gender development, behaviors, reproductive capabilities, and sex ratios.
54
What is sexual differentiation?
Sexual differentiation is the embryonic process of developing into a male or female, which includes the development of internal and external genitalia and the brain.
55
Who discovered the paradigm of sexual differentiation, and what are the three stages of sex differentiation he described?
Alfred Jost discovered the paradigm of sexual differentiation. The three stages are chromosomal sex (XX, XY), gonadal sex (genitalia), and phenotypic sex (morphology, function, and behavior).
56
What role does the Y chromosome play in sexual differentiation?
The presence of the Y chromosome drives male development through the SRY gene in mammals. Without a Y chromosome (XX), female development occurs.
57
What hormones are secreted by males during sexual differentiation, and what are their effects?
Males secrete anti-Müllerian hormone (AMH) and testosterone. AMH causes the Müllerian duct (primordial female reproductive system) to regress, while testosterone promotes the formation of the Wolffian duct (primordial male reproductive system).
58
How do estrogens and androgens coordinate sexual differentiation?
Sexual differentiation is coordinated largely by estrogens and androgens, which regulate the development of internal and external genitalia and the brain.
59
What are the potential effects of inappropriate exposure to EDCs during sexual differentiation?
Inappropriate exposure to EDCs that mimic or block estrogens and androgens can cause irreversible effects on the brain, the internal reproductive tract, and the external genitals.
60
What evidence exists for the effects of EDCs on sexual differentiation in laboratory animals, wildlife, and humans?
Evidence is clear in laboratory animals and wildlife, but equivocal in humans. Epidemiological evidence in humans includes increased incidences of cryptorchidism, hypospadias, decreased semen quality and quantity, increased incidence of testicular and prostate cancer, and increased incidence of cancers in estrogen-responsive tissues in women (breast, ovary, uterus, cervix).
61
How is developmental toxicity assessed in laboratory animals?
Developmental toxicity in laboratory animals follows strict protocols to assess the effects of xenobiotics.
62
What methods are used in epidemiological studies of human populations for assessing developmental toxicity?
Epidemiological studies of human populations involve clinical evaluations, such as tools or biomarkers, to assess conditions like Fetal Alcohol Spectrum Disorders (FASD).
63
What are some alternative testing approaches proposed for developmental toxicity, and what challenges do they face?
Alternative testing approaches include in vitro cell culture, embryo culture, and non-mammalian animals. These approaches face challenges due to the complexity of human embryogenesis and the large number of xenobiotic targets, making them unrealistic for comprehensive testing.
64
What is neoplasia?
Neoplasia is the new growth or autonomous growth of tissue.
65
What is a neoplasm?
A neoplasm is the lesion resulting from neoplasia.
66
How is a tumor defined, and is it always neoplastic?
A tumor is a lesion characterized by swelling or an increase in size and may or may not be neoplastic.
67
What are the characteristics of benign lesions?
Benign lesions are characterized by expansive growth, often exhibiting slow rates of proliferation that do not invade surrounding tissues.
68
What distinguishes malignant lesions from benign lesions?
Malignant lesions demonstrate invasive growth and are capable of metastasizing to other tissues and organs.
69
What are metastases?
Metastases are secondary growths derived from a primary malignant neoplasm.
70
What is cancer?
Cancer is a malignant neoplasm.
71
Define carcinogen
A carcinogen is a physical or chemical agent that causes or induces neoplasia
72
What is a genotoxic carcinogen?
A genotoxic carcinogen is a substance that interacts with DNA, resulting in mutations.
73
What is a nongenotoxic carcinogen?
A nongenotoxic carcinogen is a substance that modifies gene expression without damaging DNA.
74
What is lifestyle carcinogenesis, and what are some modifying factors?
Lifestyle carcinogenesis refers to cancer caused by lifestyle factors, such as diet, nutrition, obesity, exercise, and tobacco use.
75
Where does the evidence for cancer-causing chemicals come from?
Evidence for cancer-causing chemicals comes from human data (usually epidemiological) and laboratory animals (dose-response experiments).
76
Group ___: Agent is carcinogenic to humans (strong human and animal data).
1
77
Group ___: Agent is probably carcinogenic to humans (suggestive human data, positive animal data).
2A
78
Group ___: Agent is possibly carcinogenic to humans (weak human data, positive animal data).
2B
79
Group ___: Agent is not classifiable to humans (inadequate human and animal data).
3
80
Group ___: Agent is probably not carcinogenic to humans (negative human and animal data).
4
81
How is cancer described in terms of its complexity and variety?
Cancer is a complex, multifactorial disease with over 200 types.
82
What are some general mechanisms by which cancer develops?
Failure of ____ ____: Malfunction in the repair of damaged DNA.
Failure of _____: Inability to properly execute programmed cell death.
Failure to terminate cell ________: Uncontrolled cell division and growth.
DNA repair
apoptosis
proliferation
83
What happens during the initiation stage of carcinogenesis?
During the initiation stage, if a cell with altered DNA undergoes mitosis, the mutation is retained, and the cell is "initiated," meaning it becomes a tumor cell with altered genotype and phenotype. This is an irreversible event.
84
What role do proto-oncogenes and tumor suppressor genes play in neoplasia?
Neoplasia often occurs when proto-oncogenes are converted (activated) to oncogenes through mutation. Additionally, if tumor suppressor genes are inactivated through mutation, it can lead to neoplasia.
85
Why is the p53 tumor suppressor gene significant in cancer?
The p53 tumor suppressor gene is mutated in about half of all human cancers and is known as the "guardian of the genome." It plays a critical role in preventing cancer development.
86
What occurs during the promotion stage of carcinogenesis?
During the promotion stage, an initiated tumor cell may remain dormant for a long period but begins to proliferate in the presence of promoters. Promotion is a reversible phenomenon, unlike initiation.
87
What are some examples of promoters in the promotion stage?
Examples of promoters include toxicants, hormones, calories, and ethanol.
88
What characterizes the progression stage of carcinogenesis?
The progression stage involves the conversion of a benign tumor to a malignant tumor, which is an irreversible process. It involves complex genetic alterations such as chromosomal aberrations, both in the number of chromosomes (aneuploidy) and their appearance/morphology (karyotype).
89
Why do rapidly dividing cells make more mistakes during the progression stage?
Rapidly dividing cells make more mistakes because the increased rate of cell division leads to a higher likelihood of genetic errors and abnormalities.
90
How do genotoxic carcinogens generally become active?
Most carcinogenic chemicals are inactive procarcinogens that must be bioactivated to yield reactive metabolites (ultimate carcinogens), such as epoxides.
91
What genetic changes are often involved with genotoxic carcinogens?
Genotoxic carcinogens often involve the activation of proto-oncogenes (e.g., Ras) and the inactivation of tumor suppressor genes (e.g., p53).
92
How do nongenotoxic carcinogens promote cancer, and what is their effect on DNA?
Nongenotoxic carcinogens promote cancer by acting as promoters of mitosis and/or inhibitors of apoptosis. They do not damage DNA and are also referred to as epigenetic carcinogens because they likely involve DNA methylation.
93
What are some examples of nongenotoxic carcinogens?
Xenobiotic mitogens (e.g., DDT, PCBs, cadmium)
Endogenous mitogens (e.g., estrogens, androgens, growth factors)
Xenobiotics that cause sustained cell injury (e.g., chloroform)
94
What are cocarcinogens, and how do they affect carcinogenicity?
Cocarcinogens are substances that are not carcinogenic themselves but increase (potentiate) the effect of a carcinogen, mainly through effects on ADME
95
Provide an example of a cocarcinogen and its effect.
An example of a cocarcinogen is ethanol, which induces the CYP2E1 enzyme involved in the bioactivation of a procarcinogen.
96
What are solid state carcinogens, and what are some examples?
Solid state carcinogens are substances that cause cancer through continuous physical irritation, oxidative stress, and/or excessive fibrosis. Examples include asbestos and silica (quartz dust), both of which are Group 1 carcinogens known to cause lung cancer.
97
What are complete carcinogens, and what stages of cancer do they affect?
Complete carcinogens are xenobiotic mixtures that consist of chemicals involved in all three stages of cancer (initiation, promotion, and progression).
98
Provide examples of complete carcinogens.
Examples include tobacco smoke and ethanol. Exposure to both can cause a synergistic effect on carcinogenicity.
99
What are some examples of metals known to be carcinogenic to humans?
Examples include arsenic (As), beryllium (Be), cadmium (Cd), chromium (Cr), and nickel (Ni), all of which are Group 1 carcinogens in humans.
100
What mechanisms are likely involved in the carcinogenicity of metals?
Carcinogenic mechanisms for metals are complex and may involve both genotoxic and nongenotoxic pathways, with reactive oxygen species (ROS) production and oxidative stress playing key roles.
101
How do genotoxic and non-genotoxic carcinogens differ in their mutagenic potential?
Genotoxic carcinogens are mutagenic and cause direct DNA mutations, while non-genotoxic carcinogens are non-mutagenic and do not cause direct DNA damage
102
Explain the concept of a threshold for non-genotoxic carcinogens.
Non-genotoxic carcinogens are considered to have a threshold dose below which they do not cause cancer, and their effects can be reversible.
103
How does the dose-response relationship of non-genotoxic carcinogens compare to that of genotoxic carcinogens?
Both types of carcinogens have a dose-responsive tumorigenicity, meaning the likelihood of tumor formation increases with the dose.
104
At which stage of cancer development do non-genotoxic carcinogens typically function?
tumor promotion stage
105
Can non-genotoxic carcinogens act as complete carcinogens?
Non-genotoxic carcinogens are typically not considered complete carcinogens because they mainly function at the promotion stage and do not directly initiate or progress cancer.
106
What role does species, strain, and tissue specificity play in the effects of non-genotoxic carcinogens?
The effects of non-genotoxic carcinogens can vary depending on the species, strain, and tissue involved
107
Why are certain organs targets of xenobiotics?
Certain organs are targets of xenobiotics due to their specific functions in metabolism, detoxification, and excretion. The liver, for example, has resident macrophages (Kupffer cells) that release pro-inflammatory mediators and is involved in the biliary excretion of xenobiotics.
108
What role do Kupffer cells play in the liver?
Kupffer cells are resident macrophages in the liver that release pro-inflammatory mediators, which can be involved in oxidative stress
109
What is the function of bile canaliculi in the liver?
Bile canaliculi are involved in the biliary excretion of xenobiotics. They use active transport "pumps" to up-concentrate toxic metabolites by up to 5000 times in the canaliculi, as well as passive and facilitated diffusion transporters.
110
What is steatosis, and what are its causes and clinical markers?
Steatosis, or "fatty liver," is characterized by more than 5% lipid within cells. It can result from both acute and chronic exposures, is reversible, and can be caused by substances like ethanol. The clinical marker for steatosis is serum triglycerides.
111
Describe necrosis in the liver, its causes, and clinical markers.
Necrosis involves the loss of ability for osmoregulation, cell swelling, and eventually cell explosion. It can be focal or massive, usually results from acute exposure, and is irreversible. Causes include decreased ATP and altered Ca2+ regulation. Examples include acetaminophen and carbon tetrachloride. Clinical markers are alanine aminotransferase (ALT), aspartate aminotransferase (AST), and ϒ-glutamyl transpeptidase (GGT) in blood plasma/serum.
112
What is cholestasis, its symptoms, and clinical markers?
Cholestasis, involves decreased bile formation and biliary secretion. Symptoms include a yellowish tinge in the skin and eyes due to bilirubin buildup. Causes include ethanol, certain metals, steroids, and certain drugs. Clinical markers are alkaline phosphatase (ALP), GGT, and bilirubin in plasma.
113
Explain cirrhosis, its causes, and clinical markers.
Cirrhosis is characterized by extensive fibrosis throughout the liver, making it solid and hard due to scarring. It can result from chronic ethanol consumption and involves oxidative stress, mitochondrial damage, steatosis, necrosis, and fibrosis. Clinical markers are plasma ALT, AST, and GGT
114
What is hepatocellular carcinoma, and how is it diagnosed?
Hepatocellular carcinoma is a very common form of liver cancer. It is diagnosed through clinical markers such as elevated alpha-fetoprotein (AFP) in blood, biopsy, MRI, and CT scans.
115
Why is the liver particularly susceptible to toxicity from xenobiotic exposure? (6)
Increased expression of CYP presence
First organ reached
Enterohepatic cycling
Preferential distribution
Specialized macrophages
Active transport systems
116
How can researchers experimentally investigate complex toxic mechanisms in the liver?
"Knockout" models, which involve genetically engineered organisms that have specific genes turned off, are powerful experimental tools in mechanistic toxicology.
117
Why are anatomy and physiology important considerations for target organs like the liver?
The anatomy and physiology of a target organ determine its form and function, influencing its susceptibility to toxic effects from xenobiotics
118
What are the most common hepatotoxic effects observed in the liver? (5)
Steatosis (fatty liver)
Necrosis
Cholestasis
Cirrhosis
Carcinogenesis (neoplasia)
119
Why is the kidney a major target organ for xenobiotics?
Major excretion route for most xenobiotics.
Highly perfused organ.
Concentrates xenobiotics in the filtrate.
Transports xenobiotics across tubular cells.
Moderate expression of biotransformation enzymes
120
What are the major functions of the kidney?
Volume (pressure)
Concentration
PH - acid base balance
Metabolic (vitamin D)
Excretory - nitrogenous bases
Endocrine
121
What are some major examples of nephrotoxicants?
Certain heavy metals, halogenated hydrocarbons, and drugs (especially antibiotics and analgesics) are major examples of nephrotoxicants.
122
Why are proximal convoluted tubule (PCT) cells particularly susceptible to nephrotoxicants?
Tubular transport of many xenobiotics occurs in PCT cells, leading to accumulation.
PCT cells have the greatest CYP enzyme activity among kidney cells.
They have high metabolic activity (lots of mitochondria).
123
Which other kidney cells are susceptible to nephrotoxicity?
Glomerular cells are also susceptible to nephrotoxicity
124
How can urinalysis be used to test kidney function?
Proteinuria
Glycosuria
Functional enzyme tests
125
________: Increased levels of small proteins indicate loss of PCT reabsorption (toxicity to PCT cells). Increased levels of large proteins indicate effects on glomerular cells (decreased glomerulus function).
Proteinuria
126
________: Increased glucose in urine indicates tubular dysfunction in the absence of hyperglycemia.
Glycosuria
127
Functional _______ tests: For example, GGT in urine can be used.
enzyme
128
How can blood analysis be used to test kidney function?
Blood Urea Nitrogen (BUN): Increased urea in blood indicates reduced glomerular filtration rate (GFR).
Creatinine Clearance: Presence of creatinine in blood indicates impaired kidney function
129
What are the three regions of the lung that are differentially affected by xenobiotics?
Nasal passages
Conducting airways (trachea and bronchi)
Gas exchange region (alveoli)
130
What are the primary sources of lung damage caused by xenobiotics?
Oxidative stress (e.g., ozone, NO, smoke)
Gases and vapors (e.g., chlorine, ammonia, volatile solvents)
Particles and aerosols, with size being most important (e.g., PM2.5, nanoparticles)
131
Why are smaller particulates more potentially toxic to the lungs?
Smaller particulates can travel further into the lungs, making them more potentially toxic as they can reach deeper regions of the respiratory tract.
132
What are the acute effects of xenobiotic exposure on the respiratory tract?
Acute effects can be reversible or irreversible and can directly affect the respiratory tract or be absorbed systemically to cause effects in other organs.
133
What are some examples of the acute effects of xenobiotic exposure on the respiratory tract?
Airway reactivity: Contraction of bronchial smooth muscle, major concern in asthma and air pollution.
Pulmonary edema: Fluid accumulation in the lung, reducing O2/CO2 exchange (e.g., caused by Cl2, NH3 gas).
134
What are the chronic effects of xenobiotic exposure on the respiratory tract?
Chronic effects are usually irreversible and include:
Fibrosis
Emphysema
Asthma
Neoplasia
135
_______: Increased production of extracellular matrix proteins (e.g., collagen) by fibroblasts, leading to smaller, stiffer lungs and reduced gas exchange.
Fibrosis
136
_________: Breakdown of lung elastin, leading to larger, stretchier lungs with impaired alveolar gas exchange and less contraction for exhalation.
Emphysema
137
________: Increasing prevalence, especially in urban areas.
Asthma
138
________: Lung cancer, now one of the leading causes of cancer mortality, caused by factors like tobacco smoke, metallic dusts and fumes (e.g., As, Cd, Ni, Cr), asbestos, and radon gas.
Neoplasia
139
What is the most fundamental concept in toxicology and pharmacology?
The most fundamental concept in toxicology and pharmacology is the dose-response relationship.
140
What are the two main uses of dose-response relationships?
To compare drug potencies and efficacies, and to determine drug safety.
To determine toxicity thresholds of xenobiotics for use in human and ecological risk assessments.
141
What are the two main types of dose-response relationships?
Graded dose-response relationships.
Quantal dose-response relationships.
142
How are dose-response relationships typically plotted?
They are plotted with dose on the independent (x) axis and response on the dependent (y) axis
143
What is the LD50, and how is it commonly measured?
The LD50 (median lethal dose) is the dose causing death in 50% of the population, commonly measured in 4-day exposures and expressed in mg/kg.
144
What do graded dose-response relationships show?
Graded dose-response relationships show continuous responses of individuals, with the y-axis usually representing "percent response" from 0-100%.
145
What information do graded dose-response relationships provide?
They provide information about the intensity of response over a dose range and are mainly used to compare potency and efficacy.
146
What do quantal dose-response relationships show?
Quantal dose-response relationships show population responses as "all-or-none" responses, with the y-axis representing "percent of individuals responding" from 0-100%.
147
What information do quantal dose-response relationships provide?
They provide information about the number of individuals exhibiting a specified effect over a dose range and are mainly used to determine xenobiotic safety.
148
What is an example of a quantal dose-response relationship?
An example is mortality, where the frequency and cumulative response in the population can be analyzed, often using probit analysis to linearize the data.
149
What does EC50 or ED50 represent in dose-response curves?
EC50 or ED50 represents the concentration or dose causing a 50% maximal response, used to characterize drugs and compare potencies.
150
How are dose-response curves used to determine effective, toxic, and lethal doses?
Dose-response curves can be used to determine any effective dose (ED), toxic dose (TD), or lethal dose (LD) at various levels (e.g., ED1, ED10, ED20, ED99).
151
What is the shape of a typical dose-response curve?
A typical dose-response curve is sigmoidal.
152
How is efficacy defined, and how is it represented on a dose-response curve?
Efficacy is the ability of a xenobiotic to produce a maximal response. It is represented by the height of the dose-response curve, with higher efficacy resulting in a curve further up.
153
How is potency defined, and how is it represented on a dose-response curve?
Potency is the amount of xenobiotic needed to achieve a desired response. It is represented by the position of the dose-response curve along the x-axis, with more potent substances shifting the curve to the left.
154
Provide an example of relative potency and relative efficacy.
Relative Potency: Drug X is more potent because it takes a lower dose to achieve the desired response compared to Drug Y.
Relative Efficacy: Drug X is more efficacious because at its maximum dose, it achieves 90% maximal effect, whereas Drug Y only achieves a maximum of 40%.
155
What is the Therapeutic Index (TI), and how is it calculated?
The Therapeutic Index (TI) is a measure of drug safety, calculated as the ratio of the toxic dose for 50% of the population (TD50) to the effective dose for 50% of the population (ED50). It can also be calculated using the lethal dose (LD50) for 50% of the population:
TI = TD50 / ED50 or LD50 / ED50
156
What is the Margin of Safety, and how is it calculated?
The Margin of Safety is a more conservative measure of drug safety, calculated as the ratio of the dose that causes toxicity or death in 1% of the population (TD1 or LD1) to the dose that causes the desired therapeutic effect in 99% of the population (ED99):
Margin of Safety = TD1 / ED99 or LD1 / ED99
157
Why is the Margin of Safety considered more conservative than the Therapeutic Index?
The Margin of Safety is more conservative because it assesses the risk of toxicity or death at a very low dose (1% of the population) compared to the dose needed for a therapeutic effect in almost the entire population (99%). This provides a better safety margin for drug use.
158
What is hormesis, and how is it represented in dose-response curves?
Hormesis is a dose-response phenomenon where low doses of a substance can have beneficial effects, while high doses are toxic. This results in U-shaped dose-response curves, which are common for essential nutrients and vitamins.
159
How do the slopes of U-shaped dose-response curves change with sensitivity and toxicity of a xenobiotic?
The slopes of U-shaped dose-response curves get steeper when the sensitivity to a substance increases and when the substance is more toxic. This indicates a narrower range of beneficial doses before toxicity occurs.
160
What is descriptive animal toxicity testing, and what is its main goal?
Descriptive animal toxicity testing, also known as animal bioassays, aims to determine xenobiotics that have toxic effects on organisms at low (environmentally realistic) exposures. It is not limited to animals but also includes tests for microbes and plants.
161
What are the two main principles on which animal toxicity tests are based?
Effects produced in lab animals are applicable to humans, or effects produced in non-human animals are applicable to populations and communities of wildlife.
Exposure of experimental animals to high doses of xenobiotic is necessary to identify hazards to human health.
162
Why is it necessary to use high doses of xenobiotics in laboratory animal toxicity tests?
The number of animals used in tests is small relative to the size of the human population.
Higher doses are needed to ensure that the response will occur frequently enough to be detected.
163
Provide an example to illustrate the need for high doses in toxicity testing.
Detecting a cancer incidence of 0.01% (1 in 10,000 humans) would require using 30,000 lab animals, making high doses necessary to observe and measure the effects.
164
How is human cancer risk assessment typically based?
Human cancer risk assessment is based on the incidence of 1 cancer in a million people, a societal decision to ensure safety.
165
What is the most common measure for acute lethality in toxicity testing, and why is it important?
The most common measure for acute lethality is the 96-hour LD50, which determines the lethal dose causing death in 50% of the test population. It is important because it is the first test for virtually all new chemicals, providing useful information on toxicity symptoms, target organs, mechanism of toxicity, and dosing range for further testing.
166
Why are skin and eye irritation tests and skin sensitization tests rarely used today?
These tests are rarely used today due to ethical concerns. Instead, in vitro alternatives are utilized.
167
What is the common design for subacute toxicity tests, and what is its purpose?
The common design for subacute toxicity tests is a 14-day repeated dose study. The purpose is to assess the effects of repeated exposure to a xenobiotic over a short duration.
168
What is the usual duration for subchronic toxicity tests, and what is their main use?
Subchronic toxicity tests usually last around 90 days and involve two species. The main use is to determine the toxicity threshold (NOAEL) for risk assessment.
169
How long do chronic toxicity tests last, and what are they mainly used for?
Chronic toxicity tests last from 6 months to 2 years, covering a major portion of the lab animal's lifespan. They are mainly used for carcinogenicity testing and follow strict protocols (good laboratory practice; GLP).
170
What is a common problem with chronic toxicity tests in lab rodents?
A common problem is the high incidence of many cancers in lab rodents, even in the control group.
171
What is the difference between developmental toxicity and reproductive toxicity?
Developmental toxicity involves adverse effects that occur any time between conception to puberty (teratology refers specifically to effects between conception and birth), while reproductive toxicity affects the female and male reproductive systems.
172
Why are alternative models like zebrafish and Xenopus potentially useful for developmental toxicity testing?
They are potentially useful due to the similarity in embryo development and organogenesis among vertebrates.
173
What is mutagenicity, and why is it a concern?
Mutagenicity is the ability of a chemical to cause alterations in DNA or chromosomes (genotoxicity) in either somatic or germ cells. It is a concern because somatic cell mutations can lead to carcinogenesis, while germ cell mutations can cause developmental toxicities in offspring.
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What is the best-known mutagenicity test, and how does it work?
The best-known mutagenicity test is the Ames Test in Salmonella typhimurium. It uses a strain of Salmonella that requires an amino acid from an exogenous source, with enzymes in the extract that can modify the chemical being tested.
175
What is a biomarker?
A biomarker is a xenobiotically-induced alteration of cellular or biochemical components, or processes, structures, or functions that is measurable in a biological system or sample. It provides evidence of either exposure to, or effects of, toxicants.
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What types of responses can biomarkers measure?
Biomarkers can measure molecular, cellular, histological, physiological, or behavioral responses.
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What are some examples of biomarkers in human diagnostic medicine?
Prostate-specific antigen (PSA) for cancer risk.
Breast cancer susceptibility protein (BRCA) for cancer risk.
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transpeptidase (GGT) for organ damage.
178
What are some examples of biomarkers in ecological toxicology?
Serum cholinesterase activity.
CYP enzyme induction.
Vitellogenin in male oviparous vertebrates.
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What are some qualities make a good biomarker?
Non-_______(samples collected without harming the animal).
__________-based (linked to negative effects at higher levels of biological organization).
______ timing (following exposure).
________ of response (not too transient or reversible).
Applicable to _____ studies (ideally validated in the field).
invasive
Mechanistically
Suitable
Permanence
field
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What are some more qualities make a good biomarker?
________ (detects effects at earlier time points or lower exposures).
_______ (to a specific class of toxicants).
Easy to _______ (requires minimal advanced equipment or technical training).
_________ and reliable (good accuracy and precision).
___________.
Sensitive
Specific
measure
Reproducible
Inexpensive
181
What is risk assessment?
Risk assessment is the systematic scientific characterization of potential adverse health effects resulting from human (or non-human biota) exposure to hazardous agents or situations.
182
How is risk defined in the context of toxicology?
Risk is defined as the probability of an adverse outcome.
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What is risk management?
Risk management is the process by which policy actions (regulations) to deal with the hazards identified in risk assessment are chosen.
184
What is risk communication?
Risk communication is the process of making risk assessment and risk management information comprehensible to non-scientific people, such as lawyers, the lay public, and stakeholders.
185
What does No Observed Adverse Effect Level (NOAEL) represent in a dose-response curve?
NOAEL represents the highest dose that does not produce a significantly elevated incidence of adverse response compared to the control.
186
What does Lowest Observed Adverse Effect Level (LOAEL) represent?
LOAEL represents the lowest dose that produces a significantly elevated incidence of adverse response compared to the control.
187
What is Acceptable Daily Intake (ADI) and how is it calculated?
ADI is the daily intake of a chemical that appears to be without appreciable risk during an entire lifetime, based on scientific information. ADI is used for food additives, pesticides, and drugs. It is calculated as:
ADI = NOAEL / safety factor
188
What is Tolerable Daily Intake (TDI) and how does it differ from ADI?
TDI is similar to ADI but applies to xenobiotics with no reason to be in food, such as industrial contaminants. It is calculated in the same way as ADI.
189
What does the USEPA use that is equivalent to ADI/TDI?
The USEPA uses the Reference Dose (RfD), which is equivalent to ADI/TDI.
190
Why does TDI vary greatly among jurisdictions?
TDI varies greatly among jurisdictions due to differences in extrapolation methods used for risk assessment.
191
What is Lifetime Average Daily Dose (LADD)?
LADD is the average dose that humans are exposed to on a daily basis for their entire lifetime.
192
How is LADD compared to ADI/TDI to assess toxicological risk?
LADD is compared to ADI/TDI to determine if there is a toxicological risk to humans. If LADD > ADI/TDI, risk managers must make policy decisions to reduce human risk.
193
What is the High-End Exposure Estimate (HEEE)?
HEEE represents the upper 90th percentile of exposures in the human population.
194
What are Short Term Exposure Limits (STEL) and where are they used?
STEL are used in occupational settings for acute exposure to chemicals, mainly industrial solvents, to ensure worker safety over short exposure periods.
195
What are the four main objectives of risk assessment?
Balance Risk and Benefits: Examples include drugs and pesticides.
Set Target Levels of Risk: Examples include food contaminants and water pollutants.
Set Priorities for Program Activities: Examples include regulatory agencies, manufacturers, and environmental/consumer organizations.
Estimate Residual Risks: Assess the extent of risk reduction after steps are taken to reduce risks.
196
What are the four steps in the risk assessment framework?
Hazard Identification: Determine if there is a potential risk.
Dose-Response Assessment: Determine toxicity thresholds.
Exposure Assessment: Assess routes of exposure and levels of exposure.
Risk Characterization: Combine dose-response assessment and exposure assessment to characterize xenobiotic risks.
197
What are some key research activities involved in risk assessment?
Laboratory and field measurements of exposures.
Evaluation of exposed populations and observation of adverse effects.
Development of new mechanistic understandings of toxicity.
Integration of new genomic information.
198
How is hazard identification conducted in risk assessment?
Structure activity analysis.
In vitro tests.
Animal bioassays.
Epidemiological studies.
199
What factors are considered in dose-response assessment?
Relationship between dose and response.
Age of the population.
Gene-environment interactions.
200
What does exposure assessment involve in risk assessment?
It involves determining the types, levels, and duration of exposures experienced or anticipated.
201
What questions are addressed in risk characterization?
What is the nature and estimated incidence of adverse effects in a given population?
How robust is the evidence?
How certain is the evaluation?
Are susceptible populations characterized?
Is there a relevant mode of action?
202
What are some key components of risk management?
Development of regulatory options (control, substitute, inform).
Evaluation of public health, economic, social, and political contexts for risk management options.
203
How do risk assessment and risk management evolve over time?
They follow a continuous cycle of problem/context -> risks -> options -> decisions -> actions -> evaluation -> problem/context, with stakeholder engagement throughout the process.
204
What is "Quantitative Risk Assessment" in the context of dose-response assessment?
Quantitative Risk Assessment involves the characterization of dose-response curves to determine toxicity thresholds, such as NOAEL (No Observed Adverse Effect Level) and ED20 (Effective Dose for 20% of the population).
205
Why is there a need to extrapolate high dose animal bioassay data to low dose human exposures?
High dose animal bioassay data need to be extrapolated to low dose human exposures to accurately assess human health risks since humans are generally exposed to much lower doses of xenobiotics.
206
What solution is used to address the problem of extrapolating high dose animal data to low dose human exposures?
Low dose extrapolation methods and safety factors are used to address this problem. A commonly used safety factor in human health risk assessment is 100.
207
How is the safety factor of 100 derived for human health risk assessment?
Divide by 10 to account for kinetic and dynamic differences between species.
Divide by 10 again to account for kinetic and dynamic variability within the human population.
208
What are halogenated aromatic hydrocarbons (HAHs), and why are they a concern?
HAHs are highly lipophilic, resistant to biotransformation and environmental degradation, and extremely toxic (carcinogenic/teratogenic). They include dioxins, furans, and polychlorinated biphenyls (PCBs).
209
How are the concentrations of individual dioxin-like chemicals in food assessed?
Due to their common mechanism of action (binding to the aryl hydrocarbon receptor; AhR), the concentrations of individual dioxin-like chemicals in food can be simply added together.
210
How does ecological risk assessment differ from human health risk assessment?
Ecological risk assessment involves more detailed science on environmental fate, interactive effects of toxicants and other stressors, predatory-prey relationships, and food web dynamics. It focuses on protecting populations and communities of non-human species, whereas human health risk assessment focuses on protecting individual humans.
211
What societal and political questions are involved in ecological risk assessment?
Questions involve determining what level of ecosystem impairment society is willing to accept.
212
How does risk perception influence risk assessment and management?
Risk perception, especially from the general public, plays a crucial role in how risks are assessed and managed. Public perception can influence policy decisions and risk communication strategies.
