EFB400 Test 2

exposure to fungal toxins

- a new DNA sequencing technique that can detect exposure to aflatoxin B1, a substance produced by fungi that is a known liver carcinogen -this technique could lead to early detection and management of people at high risk of developing liver cancer -scientists exposed very young mice to the toxin -even at 10 weeks, a very distinct mutational signature comes up -very early-inset, not seen with other carcinogens -Chawanthhayatham comes from Thailand where a Thai-MIT study 50 years ago first connected aflatoxin in the environment with human liver cancer, a disease prevalent in that country. Her father died from the disease in 2016

Inhibition of esterases

-AChE is a very useful biomarker -useful because the degree of inhibition = toxic effects -two classes of compounds cause AChE inhibition, OPS and carbamates -causes accumulation of acetylcholine, disruption of nerve function, resulting in tremors, motor dysfunction, and death

Excretion of PFAS

-PFAs are primarily eliminated via urine with smaller amounts eliminated in feces and breast milk -the elimination halflife of PFAS compounds (the time it takes for the amount of PFAS in the bdoy to be reduced by 50%) are shorter in females than males -PFAS have also been detected in excreted menstrual fluids which may contribute to the sex differences observed in female and male PFAS serum concentration -the chemical composition, chain length, and branching of the various PFAS chemical structures impacts the excretion rates of the individual PFAS -PFAS containing sulfonates with greater chain length and branching have the slowest elimination rates comparatively

Absorption of PFAS

-PFOA and PFAS are examples of long chain perfluorinated compounds (PFCs) -animal studies have measured a very rapid absorption of both long-and shortchain PFAS orally administered to animal models -the absorption rate for PFOA in female rats was an order of magnitude faster than that in male rates (1.1 hours vs. 10 hours)

Using baby teeth as a biomarker of exposure to metals

-a 2017 study showed baby teeth from children with autism spectrum disorder (ASD) contain more lead and lower amounts of the essential nutrients zinc and manganese than baby teeth from children without ASD - the findings suggest that ASD risk may be influences by early life exposures to metals and how a child's body processes them

How do we classify biomarkers?

-a number of different ways have been suggested widely used system 1. biomarkers of exposure -exposure to risk factors -internal dose -biologically effective dose 2. biomarkers of effect -altered structure or function -clinical disease -future significance

Cautioned needed when interpreting biomarker information

-because of the complexity of biomarker chemistry and environmental exposure and illness, it is possible to measure the wrong biomarker, obtain accurate but inappropriate information and draw false or misleading conclusions

Biomarkers

-biological markers capture what is happening inside a cell or an organism at a given point in time -serve as an early warning system for your health --> e.g. high levels of lead in your bloodstream can indicate a need to test for nervous system and cognitive disorders -biomarkers are biochemical, physiological, and histological changes that can be used to estimate either exposure to chemicals or the effects of exposure to chemicals -ideally, measurement of a biomarker might provide information about internal dosage of potentially harmful substances

Green spaces and better heart health

-biomarkers of cardiovascular health were used to compare groups who lived in different neighborhoods -living in areas with more green spaces may reduce the risk of cardiovascular disease by decreasing the body's stress and boosting its ability to repair the blood vessels -individuals who live in greener areas have lower levels of sympathetic activation, oxidative stress, and a better angiogenic profile -female participants not on beta-blockers, or those who have not previously experienced a myocardial infarction show a significantly stronger association between greenness and urinary epinephrine levels -persistent exposure to greenness is conducive to cardiovascular health -evaluation of exposure to green spaces may be informative in assessing cardiovascular disease risk -in particular, women or those without a history of myocardial infarction may benefit from proximity to green spaces -408 individuals recruited from a preventive cardiology clinic -measured biomarkers of cardiovascular injury and risk in participant blood and urine -estimated greenness from satellite-derived normalized difference vegetation index (NDVI) in zones with radii of 250 m and 1 km surrounding the participant's residences -used equations to examine associations between greenness and cardiovascular disease biomarkers. Adjusted for residential clustering, demographic, clinical, and environmental variables -in fully adjusted models, contemporaneous NDVI within 250 m of participant residence was inversely associated with urinary levels of epinephrine and F2 isoprostane -stronger associations between NDVI and urinary epinephrine in women

The "matrix" is the body fluid or tissue tested

-blood -urine -breast milk -expelled air -hair -nails -saliva -teeth -meconium -amniotic fluid -adipose tissue -other tissues and fluids

Specificity of biomarkers

-can be highly specific (ALAD is inhibited only by lead) -can be nonspecific (any chemical can cause that change) -both types are valuable

biomarkers of effect

-can be thought of as biomarkers of toxic effect -biomarkers that show an adverse effect on organisms from exposure to a chemical -e.g. DNA adducts

Why Use Biomarkers?

-clinical uses, research uses, public health uses, policy used biomonitoring approaches --> descriptive --> who is exposed, location of exposure, length of exposure, impact to society biomonitoring approaches--> risk based--> if biomarkers dose response is known --> risk analysis of results biomonitoring approaches --> risk based--> if biomarker dose response unknown--> traditional risk assessment or use modelling or animal dose

Advantages of biomarkers

-confirms absorption into the human body -measures integrated exposure -very low level exposures detectable -helps to test and validate exposure models -helps to follow exposure trends -helps to evaluate public health interventions

What are toxicity test end points?

-death: most common and used widely for regulatory purposes -increasing preferred end points: biochemical, physiological, reproductive, behavioral

Rate of absorption

-depends on fat solubility and size of the molecule -3 main locations where chemicals can be absorbed: 1. lungs 2. intestinal tract 3. skin

limitations of biomarkers

-does not define sources, pathways, or duration of exposure -cannot define toxic dose -susceptible to inferior or unscrupulous analytical laboratories -lack of meaningful reference levels -lack of toxicological and epidemiological information about the vast majority of environmental chemicals

Metabolism of PFAS

-experimental studies suggest that the 14 PFAS discussed in the recent ATSDR toxicological profile are not chemically modified or metabolized within the body

Monooxygenases

-family of proteins (enzymes) involved in metabolism or biotransformation of non-polar, aromatic, organic compounds -found in all vertebrates and invertebrates in the ER of a variety of tissues. Low levels found in plants -not restricted to any functional group -can metabolize the majority of lipophilic xenobiotics as long as they are not too large and they cannot metabolize the C-halogen bonds in PCBs and PBBs -owe their cataytic properties to the hemeprotein cytochrome P450

Human toxicity - matching exposure route

-human skin = use pig because it has similar skin physiology to humans -human gastrointestinal tract = use a monkey because intestinal physiology is more similar than rodents

Imposex and tributyl tin (TBT)

-in 1960a, TBT was used on boars, quays as molluscicides and in cooling systems in pulp and paper mills as biocides -declines of oysters and whelks in Europe and marine snails in the US -extreme cases prevents egg liberation -elevated levels of testosterone that masculinize TBT-exposed femlaes, possivle link to inhibition of cytochrom P450 -TBT is moderately lipophilic, but does not bioaccumulate in top predators such as fish, birds, and mammals because of their efficient degradation systems -in 2003, found to masculinize female fish -TBT exposure during puberty led to weigh gain, insulin resistance, increased leptin, and fatty liver in male mice -is considered an EDC in humans and is liked to obesity

Biomarkers of exposure

-indicate exposure of an organism to chemicals but do not indicate the degree of adverse effect caused by the change -e..g. cotinine in blood or urine for second-hand tobacco smoke -e..g. benzene metabolites in urine for traffic-related pollution

specificity of biomarkers

-inhibition of AChE can be used as legal proof of death by organophosphorus and carbamate pesticides --> new data shows inhibition of AChE is not caused only by OPs and carbamates, but also complex mixtures of pollutants, detergents, and metals -induction of monoozygenase is caused by a variety of chemicals and is a sensitive indicator of pollutants but does not reveal a specific cause -->exception: P4501A1 and 1A2 are induced specifically by compounds such as dioxins and coplanar PCBs --> other P450s show exposures without providing evidence of which pollutant caused the effect

Relationship of biomarkers to adverse effects

-it helps to know what adverse effect is related to a change in a biological response because we use these to track remedial actions -eggshell thinning is very predictable (16-18% is associated with population declines)

Characteristics common to animals used in acute toxicity testing

-lab hardiness -common -known life cycle -inexpensive -short lived

toxicity testing with aquatic organisms

-main organism include Daphnia -consider absorption from water and food -lab consideration: static or semi-static?

Differences in physiology affect UFA

-mice more sensitive than humans (drug used to treat hyperthyroidism is metabolized in the mouse to a potent carcinogen, but human metabolites do not cause cancer) -humans are more sensitive than guinea pigs (liver toxicology research drug is activated by the P-450 enzyme system in the liver to a carcinogen in humans but not in guinea pigs)

Functions of MFOs

-modulate and terminate steroid hormone functions -facilitate excretion of bile acids and xenobiotics -detoxification -toxification

induction of monooxygenases

-originally evolved, about 2,000 millions years ago, to handle naturally occurring toxic compounds -now they place an important role in detoxifying manmade chemicals -inducers includes OCs, OPs, pyrethroid insecticides, PAHs, PCBs, and TCDDs -induction of monooxygenases has been widely used for exposure to oil and sewage e.g., EROD induction by pulp mill effluent

What considerations does a researcher have to make when designing a toxicity test?

-routes of uptake in reality -->how will the pollutant be applied? Orally, topically, by injection? Acute vs chronic toxicity testing -can classify toxicity tests based on length of exposure -Acute toxicity tests --> time=2 days for invertebrates up to four days for fish --> not very ecologically relevant but relatively less expensive (still ~1k per test) -chronic toxicity tests -->growth, reproduction --> more relevant but more expensive -->effect at lower dose/concentration -->requires a lot of investigator effort

Choice of the appropriate matric requires understanding the absorption and metabolism of the chemical of interest

-standardized collection, storage, processing and analytical protocols are critical for meaningful results -blood, urine, breast milk, and expelled air are used most commonly -some matrices, such as hair and nails, are easily contaminated and difficult to collect in a standardized way. Therefore, results from lesser-used matrices should be scrutinized carefully to ensure they are valid measures of the exposure under study, collected properly, and analyzed by a certified lab -many biomarkers are not used or useful clinically at the individual patient level, but only for research purposes. One important reason for this is that for most environmental chemicals there are no "standard ranges" or "safe ranges" established for biomarkers -this is one of the many reasons that before ordering or interpreting a biomarker at the individual patient level, it is important to consult with experts in the field to be advised on the best way to assess environmental exposures or possible environmental illnesses in the individual patient

Toxicokinetics

-the fate of chemicals in living organisms -how a chemical acts in the body 1. uptake/absorption 2. distribution 3. metabolism 4. storage 5. excretion

L11- Toxicity Testing Learning Objectives 1. Determine NOEC, LOEC, and LC50 from a graph 2. List which traits make species useful for toxicity testing 3. identify two types of dose-response curves and determine which chemical is most toxic from the dose-response curve 4. describe the process of dose conversion from mice to humans, including assumptions

1. No observed effect concentration - concentration at which no negative effects are observed (point on the graph where there is no observed negative effects) Lowest observed effect concentration - lowest concentration at which a negative effect is observed (point on the graph where negative effects begin to occur) LC50 - concentration at which 50% of the population experiences negative effects or lethality (point on the graph where 50% mortality on the y axis meets the slope - read down to x-axis for concentration of LC50) 2. lab hardiness, inexpensive, short lived, common, known life cycle 3. Threshold - point at which below there are no observed negative effects nonthreshold- more toxic, always causing a negative effect no matter the dose on graph the one that has effect all the time is more toxic 4. start with mouse, measure highest level that has no effect, include safety factors (10% not all mice are the same, mice are not people, limited number of studies), average body weight of adult, consume 1.8l of water per day for life (80% is contaminated), WHO guideline 1 microgram/liter

L14- PFAS Learning Objectives 1. Define CECS and POPS and explain why PFAS are both 2. Know the different types of PFAS exposure in model species for human health 3. How PFAS are quantified in water, soil, and tissue samples 4. Zebrafish vs. human studies review the experiments of the two studies

1. PFAS are known as forever chemicals that persist in the environment for a long time making them a Persistent organic pollutant (POP). PFAS are also CECs because there are so many new congeners that are still being studied that don't have regulations. 2. Inhalation, ingestion starts with manufacturer waste where it is released in products, landfills, or wastewater treatment plants, it can then be inhaled or ingested by humans or it can get into other products like fire fighting foam or used to water cops where we then ingest it in our food. PFAS also get into the surface water from WWTP where it can then enter the drinking water. 3. PFAS measured from Liquid Chromatography Mass Spectrometry or other Mass Spectrometry methods 4. Zebrafish: testing cell survival, proliferation, and function in both wild caught species and zebrafish

L12 - Toxicokinetics Learning Objectives 1. Define toxicokinetics and its five components 2. describe the two phases of metabolism and xenobiotics 3. recognize a list of major classes of enzymes that metabolize xenobiotics in phase 1. Identify the group most widely used in research 4. provide an example of a pollutant that increases in toxicity after a phase 1 reaction

1. Toxicokinetics is the fate of chemicals in living organisms and how the chemical acts in the body. Absorption is the passage of a chemical across a membrane into the body (lungs, intestinal tract, skin). Distribution where a chemical goes in the body after it is absorbed. Depends on blood flow and affinity for the chemical. Metabolism is how the body increases the rate of elimination of foreign chemicals. Changes the structure of the chemical to make it polar and water soluble. Storage is where the chemical is stored in the body (liver and kidney, fat, bone, plasma proteins). Excretion is the elimination of a chemical from the body through kidneys (urine), GI tract (feces), excretion into breast milk, or exhalation and sweat and saliva. 2. Phase I of metabolism makes a chemical water soluble and polar by turning it into a metabolite through oxygenation. Phase II of metabolism makes a chemical even more polar and more water soluble making it easier to excrete from the body through the addition of amino acids. 3. monooxygenases or MFOs are the most widely used in research. Other enzymes are carboxyl esterases, A esterases, epoxide hydrolases, and reductases. 4. Organophosphates, benzo(a)pyrene, aflatoxin, vinyl chloride, and PAHS can be converted to more toxic forms during Phase I metabolism.

L13 - Biomarkers Learning Objectives 1. define biomarker and describe the two categories of biomarkers 2. explain why biomarkers are useful and limitations of their use 3. provide examples of highly specific and nonspecific biomarkers 4. be familiar with recent findings of biomarkers used to predict health outcomes

1. biomarkers capture what is happening inside a cell or an organism at a given point in time. Biological, physiological, and histological changes that can be used to estimate either exposure to chemicals or the effects of exposure to chemicals. Measurement of biomarkers provides information about internal dosage of potentially harmful substances. a chemical, its metabolite, or the product of an interaction between a chemical and some target molecule or cell that is measured in the human body. Biomarkers of exposure indicate exposure of an organism to chemicals, but do not indicate the degree of adverse effect caused by the change. Exposure to risk factors, internal dose, biologically effective dose. Biomarkers of effect show an adverse effect on organisms from exposure to a chemical. Altered structure or function, clinical disease, future significance. 2. Advantages - confirms absorption into the human body, measures integrated exposure, very low level exposures detectable, helps to test and validate exposure models, helps to follow exposure trends, helps to evaluate public health interventions limitations - does not define sources, pathways, or duration of exposure, cannot define toxic dose, susceptible to inferior or unscrupulous analytical laboratories, lack of meaningful reference levels, lack of toxicological and epidemiological information about the vast majority of environmental chemicals. 3. ALAD = specific, only inhibited by lead Inhibition of AChE = less specific, OPS and carbamates, mixtures of pollutants, detergents, and metals induction of monoozygenase = nonspecific, caused by variety of chemicals and is a sensitive indicatoor of pollutants but does not reveal a specific cause 4. green spaces and heart health (more green, less epinephrine, less stress), baby teeth for exposure to metals (ASD have more lead and less zinc and manganese in their teeth than children without ASD), exposure to fungal toxins (early detection of aflatoxin), imposex and tributyl tin (higher levels of testosterone in TBT exposed females)

L13 - Biomarkers Summary

1. biomarkers serve as an early warning system for health 2. biomarkers can tell you about exposure and adverse effects 3. biomarkers can be highly specific and nonspecific 4. research into biomarkers is important and ongoing.

L16 -Goodrum Lecture Learning Objectives 1. What are PFAS and how are they classified? 2. What are PFAS chemical properties and uses? 3. What is the EPA health advisory? Are regulatory values consistent across states and countries?

1. manmade fluorinated hydrocarbons no consensus definition extremely diverse in structure, toxicity, behavior they are classified based on polymer vs nonpolymers and based on if they have a hydrogen or not 2. high water solubility, low volatility, resistant to biodegradation, hydrophobic, oleophobic, heat resistant, stain resistant, strongest bond in nature, highly sorbent, high surface tension fire fighting foam, paper coating (food wrappers), surface treatment (water resistant fabrics), other aviation, film, electronics 3. drinking water health advisory no

L20 - Ionizing Radiation Learning Objectives 1. define ionizing radiation and describe health effects of exposure to ionizing radiation 2. list the sources of ionizing radiation 3. recognize three factors that influences health effects associated with exposure and three ways cells are affects 4. describe the source of naturally occurring radioactive gas and its primary health effect

1. radiation found in X-rays (sources are man-made and machines) or gamma rays (occur from unstable atomic nuclei) that has sufficient energy to displace electrons from molecules. Free electrons damage human cells cause illness or death cancer intellectual disability in children of mothers exposed to radiation during pregnancy heart disease and stroke 2. sources: medical imaging procedures nuclear machine procedures x rays fluoroscopy CT-scans air travel airport security screening building materials cigarette smoking and radiation radon in the home radiation from space, earth nuclear weapons testing 3. factors that influences health how fast the dose is received: impact on health won't be as bad if same does were received over long period of time opposed to all at once where the dose is received: part of the body exposure not as severe as whole body exposure How sensitive the body is to radiaiton: individual sensitivity is also a factors The cell can repair itseld and then go back to normal, the cell damage is not repaired or isincorrectly repaires, so the cell is changes which can eventually lead to cancer, there is too much damage and the cell dies 4. naturally occurring radiation gas is from the ground, building materials, air, food, the universe, and even elements in their own bodies radon gas and its decay products cause lung cancer

Dose conversion steps across species to humans - microcystin

1. starts with a mouse 2. measure the highest level that has no effect -->no observed adverse effect level (NOAEL) --> 40 micrograms/kg body weight for microcystins 3. include safety (uncertainty) factors -->10x (mice are not people) --> 10x (not every mouse is the same) --> 10x (limited number of studies) 4. average body weight of an adult (60 kg or 132 lb) 5. consume 1.8L water per day for life (80% is contaminated) 6. does not consider infant/child or at risk populations WHO Guideline value =1 microgram/liter (ppb)

L17 - Biomonitoring Learning Objectives 1. define and explain the purpose of human biomonitoring 2. know what NHANES is 3. be familiar with important findings in biomonitoring and especially from the most recent NHANES study

1. the direct measurement of people's exposure to toxic substances in the environment by measuring the substances or their metabolites in human specimens, such as blood or urine provides a measure of exposure based on internalized dose, and thus accounts for all exposure routes more directly related to adverse health effects because it reflects the amount the individual absorbed helps to create references ranges that describe general population exposures to contaminants provides context for more highly exposed groups and individuals 2. National Health and Nutrition Examination Survey began in 1971 large, nationally representative sample (interviews and Pphysical exams, subset gets biomonitoring) excellent for identifying population level exposures and trends National Biomonitoring Program National Exposure Report biannual, representative sample, separated by age, sex, race/ethnicity 3. Widespread exposure to some industrial chemicals, polybrominated diphenyl ethers accumulate in environment and human fat tissue, one type was found in all NHANES participants serums PBDEs increasing, PCBs decreasing BPA may have reproductive toxicity ongoing success in reducing blood lead levels in children mercury exposure increases with age Acrylamide is formed when food containing carbohydrates are cooked at high temperaures and as a byproduct as tobacco smoke most people exposed through diet and smoking can bind to proteins - reaction products called adducts new method to measure acrylamide and its metabolite as adducts of hemoglobin reduced exposure to environmental tobacco smoke - decreased by 70% in last 15 years

L12 Toxicokinetics Summary

1. toxicokinetics improve understanding of how a chemical acts in the body 2. MFO are an important group of Phase I enzymes that metabolize a wide range of chemicals 3. metabolism can be adaptive or maladaptive (increase or decrease the toxicity of a chemical)

L18 - Mechanisms of Toxicity Learning Objectives 1. Explain why it is important to understand mechanisms of toxicity 2. describe the major mechanisms of toxicity, the effect, and an example pollutant that causes that effect

1. uncertainty is highest when extrapolating from a LOAEL to a NOAEL - need to know mechanism of toxicity to resolve this uncertainty Facilitates: -extrapolation of animal data and in vitro data to the humans -biological monitoring and screening -understanding and predicting toxicity of new substance this aids in risk assessment and making chemicals safer 2. genotoxic effects - Form DNA adducts (covalent bond of pollutant with DNA), this causes cancer, PAHs use this mechanism *original compound is stable but after undergoing metabolism, the metabolites can bind to DNA Neurotoxic effects - disturb the normal transmission of impulses along the nerves and/or across synapses i. disrupt action potential ii. disrupt GABA receptor iii. acetylcholine mimic iv. AChE inhibitor this causes muscle tremors, convulsions, tetanus A pollutant that uses this mechanism is organophosphorus insecticides Mitochondrial poisons - eliminate the gradient of protons across the inner membrane of the mitochondria the causes ATP production to cease, cyanide uses this mechanism Vitamin K antagonists - inhibit the vitamin K cycle, this causes incomplete synthesis of clotting proteins, resulting in hemorrhage. Warfarin uses this mechanism Thyroxine antagonists - compete with thyroid hormone, cause thyroid hormone and retinol decrease, PCB metabolites use this mechanism inhibition of ATPases - interferes with osmoregulation. this causes calcium transport to be affected, Organochlorines use this mechanism Environmental estrogens and androgens - imitates estrogen or binds to the estrogen receptor. this causes masculinization of an organism. Organochlorines use this mechanism Protein sulfhydryl groups - conformational changes in proteins, this caused brain damage, methylmercury uses this mechanism

enzyme ALAD

ALAD is composed of eight subunits, each poisoned by two lead ions Lead blocks heme production through ALAD inhibition -one of the proteins poisoned by lead is involved in the synthesis of heme: 5-aminolaevulinic acid dehydratase (ALAD) -ALAD performs the first step in production of heme rings, using a zinc ion to help catalyze the reaction -as shown in the image, lead ions displace zinc ions, making the enzyme inactive. This process blocks formation of new heme groups and leads to one of the common symptoms of lead poisoning: anemia

LOEC

Concentration -lowest observed effect concentration (LOEC)

LC50/NOEC

Concentration Median lethal concentration (LC50) No-observed-effect concentration

Distribution

Distribution: where a chemical goes in the body once it has been absorbed Distribution can vary depending on where the chemical was absorbed where a chemical will be distributed depends on the blood flow to a particular tissue or organ, and the affinity of that tissue/organ for the chemical

LOED

Dose -lowest observed effect dose (LOED)

LD50/NOED

Dose median lethal dose (LD50) No-observed-effect-dose (NOED)

How do we measure toxicity?

Dose-response relationships -effects depend on doses

Storage

Four major locations that serve as storage depots: 1. liver and kidnet 2. fat 3. bone 4. plasma proteins

Monooxygenases - nomenclature

General Names -cytochrome P450 or P448 -CYP proteins -P450 monooxygenases -mixed function oxidases (MFOs) -Phase I enzymes specific names -names by gene e.g. CYPIA1 -names by substrate metabolized

Metabolism takes place in different parts of the cell

In invertebrates, phase I enzymes are found in the ER of the liver phase II enzymes are found in the cytosol (fluid component of the cytoplasm)

Major Enzymes that Metabolize Xenobiotics in Phase 1

Microsomal monooxygenases (mixed function oxidases) --> most widely used in research! carboxyl esterases A esterases Epoxide hydrolases Reductases

NOEC, LOEC, LC50 on a graph

NOEC - lowest point on graph where there is NO OBSERVED NEGATIVE EFFECT LOEC - lowest point on graph where there is the first sign of a negative effect LC50 - the point where 50% mortality meets the curve (read down to concentration for answer)

Metabolism can be detrimental

Organophosphorus insecticides become reactive metabolites called oxons during Phase 1 that can phosphorylate and inhibit acetylcholinesterase Benzo(a)pyrene, aflatoxin, and vinyl chloride become reactive during Phase I and bind to DNA PAHs can be converted to more toxic forms during phase I (becomes electrophilic and can bind to DNA

Distribution of PFAS

PFAS are distributed throughout the body via plasma, where PFAS bind to serum albumin and other plasma proteins -plasma = largest part of the blood light yellow liquid, carries water, salts, and enzymes take nutrients, hormones, and proteins to the parts of the body that need it highest PFAS concentrations are found in the liver and kidneys PFAS can pass the placental barrier during pregnancy; however, longchain lengths that contain a sulfonate group notably do not pass as readily

MFOs can have a negative effect MFO Induction: Maladaptive

Phase I: Oxidative stress, carcinogen, genotoxicity increases toxicity -oxygenation leads to the activation of procarcinogens and reactive oxygen species -gene activation leads to receptor-mediated toxicity

Phase I Metabolism

Phase I: add oxygen leads to increased polarity, reactivity -oxidation, hydrolysis, reduction resulting in the production of metabolites that contain hydroxyl groups (-OH)

MFOs can have a positive effect MFO Induction: Adaptive

Phase I: increases reactivity and polarity Phase II: conjugation and excretion decreases toxicity -oxygenation leads to excretion

Phase II Metabolism

Phase II: add amino acids leads to increased solubility and excretion -changes polar metabolite to an even more polar conjugate (negatively charged anion) with high water solubility

Metabolism Phases

Polluntant --> phase one --> metabolite--> exceretion or phase 2 --> add endogenous molecule -->conjugate-->excretion metabolite is more water soluble and then it becomes an anion after phase 2 pollutants will move into the hydrophobic parts of animals or plants unless they are biotransformed into more polar and water soluble form chemical can be excreted after phase 1 after becoming a metabolite or phase 2 after becoming conjugates (excretion) phase 1 makes it polar phase 2 makes it more polar and water soluble which is what is needed to get it out of the body

How can we reduce reliance on animal testing?

Quantitative structure-activity relationships -design of pesticides and biocides based on knowledge of chemical structure -molecules can be designed to bind to active sites of enzymes and interact with receptor sites on neurotransmitters -QSARs have been successfully developed for narcotics (use the Kow and predict fate in aquatic organisms -toxicity depends on the characteristics of sites of metabolism and action within specific organisms --> these vary greatly depending on species, strain, sex, and age --> more complex models are needed that account for species differences

Non-threshold (Y)

Y is more toxic always negative effects no matter how low the dose

Biomarker

a chemical, its metabolite, or the product of an interaction between a chemical and some target molecule or cell that is measured in the human body

Uptake/Absorption

absorption: passage of a chemical across a membrane into the body absorption must occur for toxic effects to be observed (except in some rare cases) Chemical must be dissolved to be absorbed

Bioindicator

biological responses at higher levels of organization - population, community, and ecosystem levels it is difficult to attribute biochemical changes to ecological changes (with some exceptions) and vice versa (one an ecological change has been observed it is difficult to say it happened because of a chemical cause) exceptions to the rule -eggshell thinning caused by p'p'-DDE (a DDT metabolite) resulted in reproductive failure of raptors and fish-eating birds -imposex (development by females of male characteristics) caused by tributyl tin (TBT) resulted in reproductive failure and local extinctions in gastropods

Biomonitoring helps to understand exposure

environmental monitoring media-->manmade sources--> duse, sediment, personal care--> exposure--> internal dose absorption environmental monitoring media--> natural sources--> water, air, food, soil--> exposure--> internal dose absorption exposure leading to absorption is the key step but often one of the most difficult to characterize

Excretion

excretion: elimination of chemical from the body Major sites of excretion in mammals: 1. kidneys (via urine) 2. gastrointestinal tract (through feces) 3. excretion into breast milk for mothers 4. excretion through exhalation (gases) and sweat and saliva (very minor) Excretion in vertebrates -excretion occurs via urine and /or bile and/or feces -the extend depends on the molecule weight of the xenobiotic in question --> <300 = urine --> >600 = bile *bile=digestive fluid produced by the liver and stored in the gallbladder

Metabolism

metabolism: functions to increase the rate of elimination of foreign chemicals factors that allow chemicals to be absorbed (e.g. fat solubility) reduce their elimination biotransformation allows the body to change the chemical structure of the xenobiotic. This change usually results in the chemical becoming more water soluble

Threshold (X)

more common no effect under certain dose aka there is a threshold in which before that dose no negative effects occur, but after they increase exponentially

Considerations when designing a toxicity test

one organism can be more susceptible to the toxic action of a chemical than another organism selectivity ratio = LD50 to species A/LD50 to species B

Storage of PFAS

persist for a long time in the body don't accumulate in fat

Toxicity Assessment of Noncarcinogens

reference dose (RfD) - an estimate with an uncertainty of an order of magnitude or more of a daily exposure level for the human population that is likely to be without an appreciable risk of adverse effects during a lifetime RfD = NOAEL/UFs*MFs

human biomonitoring

the direct measurement of people's exposure to toxic substances in the environment by measuring the substances or their metabolites in human specimens, such as blood or urine

Environmental monitoring

the measurement of a contaminants concentration in a medium (e.g. air soil, water, or food)

Two types of dose-response relationships

threshold (x) non-threshold (y) slope of the line = rate at which effects increase with dose slopes are equal and potency is the same, but effects occur at lower doses for non-threshold

L11 Summary

toxicity testing involves building a dose-response curve that allows us to determine dose estimates of chemicals researcher considers route and duration of exposure when designing toxicity tests, and animals traditionally have had traits that make them viable for toxicity tests 2 types of dose response relationships are threshold and nonthresold. The rate at which effects increase with dose defines the potency of a chemical many assumptions and uncertainty factors are built into deriving guidelines for safe exposures

Uncertainty Factors

used when insufficient data is available to support the use of chemical-specific and species specific extrapolation factors UFH - human variability UFA- Animal to human extrapolation UFs - subchronic to chronic extrapolation UFL - LOAEL to NOAEL extrapolation UFD - database deficiencies