week 9- environment Flashcards
• Common wastewater contaminants:
o antibiotics, perfumes, detergents, drugs, steroids, disinfectants, etc.
o surface water and ground water
o runoff from large areas → concentrated
o potential risks to human health if → drinking water
• toxicants: sources, transport/transform, removal, effects:
o S: industry, transportation, sewage plants, agriculture, fire
o T: sun, winds, clouds
o R: rain or dry deposition
o E: drinking water, human health, ground water, agriculture, smog, soils
• Airborne toxicants:
o Volatile chemicals travel far in winds
o Polychlorinated Biphenyl: similar to dioxin. Industry. carcinogenic, neurotoxin, endocrine disruptor
o PCBs: carried 1000s miles to arctic, found in polar bears and seals
o At low latitude, pollutant evaporation > deposition
o high: deposition > evaporation
• persistence:
o Some chemicals more stable, persist longer in environment
o DDT and PCBs are persistent
o Bt toxin in GM crops is not persistent
o Temp, moisture, sun, etc, affect rate of degradation
o Most toxicants degrade into simpler breakdown products
o Some of these are also toxic
o (DDT breaks down to DDE, also toxic)
• Bioaccumulation:
o Poisons accumulate in tissues
o body may excrete, degrade, or store toxicants
o Fat-soluble ones are stored.
o DDT is persistent and fat soluble → builds up in tissues
o → can move up the food chain
• Biomagnification:
o Poisons move up the food chain
o At each trophic level, chemical concentration ↑= biomagnification.
o DDT conc ↑ from plankton to fish to fish-eating birds
• Dose-response analysis:
o to determine toxicity by measuring response to different doses
o Lab animals used →Mice and rats breed quickly
o relevant to humans dt shared mammal physiology
o plotted on dose-response curve
• dose-response curve:
o threshold= dose at which response begins
o LD50= dose lethal to 50% of test animals
o Allow to predict effects of higher doses
o Extrapolation: predict how will affect humans at various conc
o usu response ↑ w dose
o OR: curve may not be linear
o endocrine disruption: may ↓
• endocrine disruption:
o Some chemicals in vivo “mimic” hormones
o Can bind → inappropriate response
o Normal: hormone system works w tiny conc
o → so it can respond to tiny conc of toxicants
• Signal words:
o relative acute toxicity of pesticide seen on label
o The (toxicologically) appropriate signal word MUST appear on every pesticide label
o The three possible signal words are:
o 3 words: danger, warning, caution, (notice?), (poison)
• CAUTION:
o lowest toxicity o All pesticides w LD50 > 500 mg/kg must display o 2 groups: o “Relatively nontoxic” (>5000) o “slightly toxic” (500 – 5000)
• WARNING:
o intermediate toxicity
o All pesticides w LD50 50-500 mg/kg must display
o = “moderately toxic”
• DANGER, POISON:
o highest toxicity
o All pesticides w LD50 ↓ 50 mg/kg must display
o = “highly toxic”
o POISON= same thing, Legally defined term
o Label must have both “DANGER” and “POISON”
o also skull and crossbones icon
• factors affecting toxicity:
o Sensitivity to toxicant can vary w sex, age, weight, etc
o Babies, older, poor health → more sensitive
o acute = high exposure in short period of time
o chronic = lower amounts over long period of time
• synergistic effects:
o Substances can interact when combined
o → mb effects greater than sum of their individual effects
o Challenge: no way to test all possible combinations!
o → environment has complex mixtures of many toxicants
• Exposure:
o route (site) helps determine dose: diff routes → diff rates of absorption o Ex: Dermal (skin), Inhalation (lung), Oral ingestion (GI), Injection o route important if there are tissue-specific toxic responses → local or systemic o Time: how long exposed o Duration and freq contribute to dose, both may alter toxic effects o Acute = usu single exposure o Chronic = mult exposures over time (frequency)
• Transport and storage of toxins on body:
o T: Lymphatics, blood; usu via blood protein that binds toxicant, eg a lipoprotein
o S: Liver, Lungs, Kidneys, Bone, Adipose (fat)
o mb stored in one reservoir, later transported elsewhere
o Storage site may or may not be site of toxic effect
o Pb stored in bone, but toxic to liver
o DDT stored in fat but toxic via prolonged gradual release
• Detoxification in vivo:
o Some chem transformed/metabolized to aid excretion o Detox → less toxic metabolic product o Kidney → urine o Liver → feces, bile o Lung → expired air
• Types of toxicants:
o Carcinogens → CA
o Mutagens → mutations in DNA
o Teratogens → birth defects
o Allergens → unnecessary immune response
o Neurotoxins: damage nervous system
o Endocrine disruptors: interfere w hormones
• Environmental toxicity assessment:
o Toxin exposure hx most important factor to determine appropriate testing
o Detailed chronological hx, determine jobs, hobbies, geographical areas
o Acute & Chronic:
o In utero
o Childhood: vaccines, meds, food, water, air, environment, hobbies
o Dental: Hg, Ni
o Workplace: sick-buildings, agriculture, industry, military
o Age of house: Pb paint phased out 1978 (now only 0.06% Pb allowed)
• Heavy metal toxicity:
o Pb, Hg, Cd, As, Mn, Ni → Inorganic and Organic salts
o Heavy metals = protoplasmic poisons
o Impair cell fxn
o Astringent, corrosive, caustic to skin
o Lethal to microorganisms
o Accumulate in body on chronic exposure
o Damage liver, kidney, bone marrow, GI mucosa, neurons, skin
o not immediately recognized dt wide range of non-specific sxs
• mecanisms of heavy metal toxicity:
o usu mult o inhibit/potentiate Enzyme/cofactor o Disrupt membrane, transport processes o Disrupt mitochondrial fxn → fatigue o ↓ neuronal fxn & nerve conduction o Ability to bind to -SH groups on proteins & amino acids
• Lab tests for heavy metals:
o Hair o Serum o RBC analysis o Urine challenge: DMPS, DMSA o Blood chem, CBC, CC, CMP o Genetic: detox, cord blood, placenta
• Blood tests for heavy metals:
o Best for short-term acute exposure
o Metals cleared rapidly from blood, accum in storage depots
o T1/2 blood (days): long term deposition
o Pb 30-60 d: bone 25 yr
o Cd up to 120 d: liver & kidney 10-20 yr
o Hg 60-70 d: organic forms lipid soluble adipose, PNS, CNS for yrs
o As 2-12 hrs: liver, kidney, muscle, skin, brain
o Mn 10-42 d: bone and brain
o Ni 24 hrs: lungs, thyroid, adrenals
• Serum “normal” levels heavy metals:
o As: 0.0 – 62 g/L o Cd: 0.0-5.0 g/L o Pb: kids ↓ 5 g/dl, adults ↓25 o Mn: 4.2 –16.5 g/L (whole blood), 0.0-7.8 (serum) o Hg: 0-60 g/L o Ni: 0.6-7.5 g/L
• Hair test for heavy metals:
o 1979 EPA: “hair is representative tissue for biological monitoring of most toxic metals”
o 2001 JAMA: UNRELIABLE
o Best as screening test (but not for Pb in kids)
o (+) MUST confirm w blood or provocative urine testing
o CDC, for kid Pb poisoning: 57% sens, 18% false (-)
o High inter-lab variability
• Impaired Hg excretion:
o Collected first hair cuts in fully immunized infants
o 94 autistic kids, 45 controls
o Average Hair Mercury: 0.25mcg/g in autistic kids
o 4.90mcg/g in controls
o Autistic kids ↑ prenatal Hg exposure
o Autistic kids have inherent problem excreting heavy metals → large risk toxicity w very small exposures
• Genetic findings in autism:
o MTHFR, ADA: ↓ glutathione
o GST M1-null: ↑ susc Hg and xenobiotic toxicity, ↑ body burden Hg
o ALAD: ↑ susc Pb toxicity; ↑ body burden Pb
o PON-1: ↑ susc pesticide toxicity
o HLA-DR4: ↑ allergy and intolerance to heavy metals
• Urine tests for heavy metals:
o Best test for chronic toxicity (most cases)
o Random: indication of “ambient” levels
o Provocative challenge test:
o best estimate of body burden
o no good test for accurate total body heavy metal burden
• chelating agents:
o for reduction of body burdens of toxic metals.
o DMPS, DMSA, D-Penicillamine, EDTA
o chemically bind w (chelate) metals, minerals, chem toxins
o actually encircles a mineral or metal ion, excrete via urine and feces
• Desirable Attributes for Chelating Agents:
o Gain access to the metals o Tightly bind and control metals o Not injure recipient o Accelerate mobilization/ removal of metals o Cheap o Easy to administer
• Chelating agent effectiveness, depends on:
o 1) affinity of chelator for the metal
o 2) distribution of chelator to parts of body where metal is
o 3) ability of chelator to mobilize metal from body once chelate is formed
• DMPS, DMSA affinities for metals:
o DMPS: Hg, Pb, Ag, Cd, Ni, As, An, Cu, Mo, Zn, Mn
o DMSA: Pb, Cd, Hg, Ag, Ni, As, Mo, Cu, Zn, Mn, Fe, Tin
• FDA-approved chelating agent:
o Ca-Na2-EDTA: 1950s
o DMSA: for Pb poisoning in kids, 1990
o DMPS: NOT FDA approved (Informed consent required!!)
• Ca-Na2-EDTA:
o Oral: only ~ 5-10% absorbed. Not appropriate for challenge test
o Suppositories: Not optimal for challenge testing; effective for long-term detox of Pb
o Urine levels (↑) after IV EDTA:
o Pb 147x, Zn 32x, Mn 15x, Fe, Cd 7x, An 4x
• DMPS:
o 2-3-dimercapto-1-propane sulfonate
o Official drug in Soviet Union since 1958, registered w German health authorities (Dimaval)
o T1/2 oral ∼ 9 hr (~ 50 % absorbed )
o T1/2 IV ↓1 hr
o Minor penetration into RBCs
o Principal route of excretion is renal
o CMP, CBC, CCLR (renal creatinine clearance) required before administration
o Affinity for Hg
o Don’t use if sensitive to sulfur compounds
• DMPS Urine Provocative Challenge Test
o Baseline 24 Hr urine tested for toxic elements
o Provoked 6-hr urine tested
o 250 mg (50 mg/ml) DMPS given by IV push
o Dental techs: 5 ug Hg/ 6 hr (before) → 424 (after)
o Dentists: 3, 162
o Controls: 1, 27
• DMSA:
o 2-3-Dimercaptosuccinic Acid (Dithiol/dimercapto cousin to BAL)
o Least toxic of this class
o Synthesized 1940’s by British chemist L.N. Owen
o Extensively investigated by the Chinese
o Oral (peds rectal), Water soluble, active in extracellular space
o CMP, CBC, CCLR required first
o Determine sensitivity to sulfur drugs
• DMSA elimination:
o Absorption rapid but variable ~25-49%
o Rapid hepatic metabolism. ~90% cysteine disulfides, ~10% unchanged
o ~75% renal elimination in 24 hr (↓2 d half life)
o ~40-80% fecal elimination
• DMSA application:
o Affinity: highest → Pb, Hg, As, Cd, Ni → lowest
o Urine Provocative Challenge Test
o FDA to tx Pb poisoning in kids
o Dose: 30 mg/Kg/d divided in three doses (10 mg/Kg po TID)
o Duration: per blood levels or clinical judgment. Many protocols exist
• DMSA potential side effects:
o Transient ↑ liver enzymes
o Thrombocytosis
o Nausea
o Reversible neutropenia, dose dependent
• Sources of Pb:
o Lead Paint o Dust, Soil o Water (Pb pipes) o Industry o Hobbies o Traditional Ethnic Remedies o Gasoline (tetraethyl Pb): rid of Pb gas → ↓ blood Pb levels
• NOEL:
o No observable effect level
o no toxic threshold for Pb
o =no measurable level of Pb in body below which no harm occurs
• Pb absorption:
o Orally consumed Pb abs in place of Ca
o Kids: 30-50% of Pb
o Adults: 5-10% of Pb
o ↑ during Pg
o crosses placenta & BBB
o BBB not complete until 6 mos → absorbed by CNS of fetus, infant
o ↑Abs 5-10x in infants and young kids than adults
• Pb toxicity:
o Ssx: Irritability, anorexia, malaise, HA, constipation, abd pain “lead colic”, renal toxicity
o “Acute lead encephalopathy” dt very high exposures = cerebral edema, ↑intracranial pressure → death
o ↓: IQ, nerve conduction, Vit D metabolism, Hb synthesis
• Mechanisms of Pb toxicity:
o Pb binds enzymes w functional sulfhydryl groups → deactivates → impair oxidative balance
o Inhibits: porphobilinogen synthetase, globin synthesis → coproporphyrin and ALA spill into urine
o Anemia: usu micro/hypo, basophilic stippling, mb ↑ serum Fe
• Blood test for Pb:
o #1 for screening recent Pb exposure EDTA tube
o “Normal” for kids is ↓5 g/dl, adults ↓ 25
o If ↑, must report to Oregon Health Division
o 10-70: provide care
o > 70: hospitalize, chelation therapy
• Pb test sources:
o Whole blood: conc 75x > serum or plasma, highest correlation with toxicity. preferred test to detect Pb exposure
o Hair: in apparent steady-state lead balance, correlates w blood Pb. Normal ↓5 μg/g. > 25 = severe Pb exposure
o Urine: ↑ w Pb poisoning, but urinary elimination occurs for many d after a single exposure
• Pesticides:
o chems used to kill or control insects, weeds, fungi, rodents, microbes
o = Insecticides, herbicides, fungicides, rodenticides, etc.
o sprays, liquids, powders, granules, baits, foggers (total release aerosols)
o Humans exposed w manufacture, mixing, applications of pesticides
o Inhalation, Ingestion, Eye & skin contact
• types of pesticides:
o insecticides: Cholinesterase Inhibitors (Organophosphates and Carbamates), Organochlorines, Pyrethroids
o herbicides: glyphosphate, Cholinesterase Inhibitors
• cholinesterase inhibitors:
o Organophosphates (OPs) & carbamates (CMs):
o Cholinomimetic: inhibit ACh-esterase enzyme
o ACh builds up in synapses, overexcites nervous system
o → rapid twitching of some muscles, paralyzed breathing, convulsions, death (extreme)
o Ops in chem warfare, nerve agents: Tabun, Sarin, Soman, VX
o Ssx: SLUDGE: salivation, sweating, lacrimation, urination, diarrhea, gastric motility, emesis
• Physiology of CIs:
o Act in mins-hrs, depends on exposure level
o inhibit either plasma pseudocholinesterase or RBC cholinesterase
o Pseudo ↓ more rapidly, but recover more quickly than RBC cholinesterase
o ↓ Pseudo: Hepatitis, cirrhosis, malnutrition, chronic alcoholism, OCPs
o ↓ RBC cholinesterase: Hemolytic anemia
• Tests for CI exposure:
o Do both: plasma and whole blood
o Baseline when worker not exposed for at least 30 d
o RBC (true) cholinesterase, whole blood; identical to acetyl cholinesterase found in synapses; better reflection; CNS gray matter
o Plasma (pseudo) cholinesterase; not identical; easy to assay; CNS white matter
o 15-25% ↓ CI: slight poisoning
o 25-35%: mod
o 35-50%: severe
• Orgnochlorines:
o DDT, DDE, insecticides
o Dichloro-diphenyl-trichloroethane
o Moderately toxic, DDT banned in US in 1972, unless public health emergency (eg malaria outbreak)
o 2004- banned world wide for agriculture (but India, N Korea, other)
o used mainly to control mosquito-borne malaria
• toxicity of DDT:
o DDT → soil, runoff, streams, fish →concentrate in predatory animals
o Acute: (low-mod exposure) N/D, ↑ LFTs, irritation (eyes, nose, throat), disturbed gait, malaise, excitability; (high) tremors, convulsions
o Chronic: assoc maternal DDT blood levels & miscarriage; Blood & breast milk can be analyzed for DDT & DDE
• DDT storage in body:
o Metabolites readily stored in adipose
o DDE: fat bx, metabolite implicated in breast CA, Liver CA death
o DDE= 1,1-dichloro-2,2-bis(p-dichlorodiphenyl)ethylene
o DDD =1,1-dichloro-2,2-bis(p-chlorophenyl)ethane
• Organochlroine testing:
o Fat, blood, urine, semen, breast milk
o blood and urine: easy, may show low, mod, hi exposure
o can’t show exact amount of exposure, or predict chance of health effects
• glyphosate:
o =”Roundup” (Monsanto)
o =Broad spectrum herbicide to kill crop weeds
o Non-selective, kills all plants: grasses, broad leaf, woody plants
o extremely difficult to measure in environmental samples
o “Roundup Ready” crops engineered to withstand exposure to glyphosate
o allows herbicide applications after crop emergence, killing weeds but not crops (ex: soybeans)
• glyphosate toxicity:
o Acute toxicity is very low
o Acute Oral LD50 = 4,300 mg/kg
o Other toxins in Roundup: various surfactants (polyoxyethyleneamines, POEAs)
o POEAs =serious irritants of respiratory tract, eyes, skin, contaminated w dioxane, a suspected carcinogen
• 24-hr urine glyphosate:
o to monitor exposure
o farmers: 233 parts per billion (ppb) the day it was used
o Non-hodgkins lymphoma pts 2.3x likely to have had contact with glyphosate
• Chlorophenoxy herbicides:
o “Agent orange” = 50-50 mix of two chemicals (2,4,D & 2,4,5,T)
o was mixed w kerosene or diesel fuel & dispersed by aircraft spraying
o 19 million gallons used in S Vietnam in Vietnam War
o contaminated with TCDD, or dioxin → health concerns
o Now banned
o Brand= “Crossbow” (2,4-d)
• Chlorophenoxy herbicides toxicity:
o Acute exposure: stomach pains, V/D
o Chronic: Carcinogen, may cause reproductive problems
o Monitor exposure: GLCT of blood, urine, ASAP bc excreted in 24-72 hrs
