Environmental Medicine (week 6 & 7): Heavy Metals
MECHANISMS BY WHICH HEAVY METALS CAUSE TROUBLE
competitive binding or absorption with minerals
inhib enzymes, inhib enzyme synthesis
usu interacts with SH sulfhydryl groups
interference with cellular organelles (ER: cadmium, mercury; lysosomes: cadmium; mitochondria: arsenic, lead; nucleus: lead)
METALLOTHIONEINS (MTs)
naturally occurring metal binding proteins
bind nontoxic and toxic metals
ubiquitous in living species
rich in cysteine (thiol groups, contain sulfur)
produced mainly in liver, kidneys
fx: prevent xenometallic toxicity, incorporation of physiologic metals (Zn, Cu, Cr3+), protect vs oxidative stress
there is a genetically determined level of MT production-->individual metal susceptibility
metal toxicity occurs when available binding sites of MTs are full, excess metals spill into tissues
upreg of MT production in chronically exposed species leads to incr resistance to toxicity: hormesis
measurement of gene expression, SNPs is fertile area for research
HEAVY METALS
effects: cancer, immune dysfx, nervous, resp, hepatic, renal damages, derm
he skipped the slide summarizing which metals have which specific effects
Arsenic is #1 concern, v toxic, next: lead, mercury, vinyl chloride, PCBs, benzene, cadmium
ctd: PAHs, benzo(a)pyrene, benzo(b)fluoroanthene, chloroform, etc
kidneys are primary emunctory for Cd, Co, Cr, Mg, Pb, Sn, Zn
high concentration of metals outside tubules-->accumulation of toxics
pH of urine affects filtration: ionic metals and H+ gradient (more acidic reduces elimination)
ARSENIC
atomic #33, row 3 under nitrogen
metallic looking mineral, grey with yellow & orange specks
2 forms: organic (with carbon) and inorganic (As2O3, As2S3, As4S4, AsH3, H3AsO4, etc)
found in: mines, volcanic soils and ash, groundwater and soil deposits
byproduct of mining for lead, gold, zinc, copper, cobalt, nickel, etc.
uses: paint/pigments, insecitcides, herbicis, semiconductors (gallium arsenide), wood preservative
www.ewg.org/node/8288 ten safety steps to reduce exposure from wood
www.safe2play.org safe playgrounds project
MEDICAL USES OF ARSENIC
Donovan's solution (AsI3) for rheumatism, malaria, TB, arthiris, Diabetes
Fowler's solution (Hk2AsO3) tonic (1909) for syphilis, malaria, vexation
Current uses: anti-parasitic, Oncology (AML)
Homeopathy
EXPOSURES TO ARSENIC
soil: mining, wood treatment, landfills
water: natural, industrial and agricultural
air: burning of treated wood
food: average consumption 50mg/day dt pesticides, insecticides, bio-accumulation (fish)
tobacco smoke (treated with pesticides)
"pressure treated wood" is major source of contamination, chromated copper arsenate (CCA)
resisted to insects, mold, bacteria, etc, banned as of 2004
(as a river guide I lived in sheds not intended for human occupation and believe this is where my arsenic burden came from)
wood preservatives leach into soil and groundwater
burnt this wood can be lethal @ ingestion of 20 grams of ash (under 1 oz); dermal contact-->ingestion from hands
STANDARDS
OSHA PEL: 0.01mg/M3
Lethal: 1mg/kg
ARSENIC TOXICITIES
Organic As (As) < Arsenate +5 < Arsenite +3 < AsH3 (arsine gas most toxic, industrial, mining, causes extremely rapid hemolysis of RBCs)
sx: rapid weakness, dyspnea, juandice, fever, myalgia, N/V/D
chemical reactivity similar to phosphorus
substitutes in biochemical and physiologic rxns
ARSENIC HEALTH EFFECTS
ACUTE EFFECTS
TRIAD: hemolysis, abdominal pian, hematuria
resp irrit
GI hyperpermeability, necrosis, hemorrhagic gastroenteritis
hepatic necrosis, portal hypertension
renal tubular necrosis, renal failure
bone marrow suppression, pancytopenia
spontaneous abortion, miscarriate
CHRONIC EFFECTS
patchy skin pigmentation: neck, eyelids, axilla, areolae
hyperkeratosis palsm and colds, corns
Mee's lines (across nail beds)
glove and stocking paresthesia, peripheral sensory axonopathy
blackfood disease: gangrene due to damaged capillaries
overlap with raynaud's, more if smoker
As5 competes with phosphorus, interferes with bone formation and ATP genesis
As3 interferes with Krebs cycle (energy) and sulfur metabolism (reduces GSH)
muscle weakness, myalgias, headache, light headed
garlic odor, salivation, lacrimation
cold sweats, stomatitis, pruritis, sore throat
ARSENIC CARCINOGENISIS
lung skin, bladder, kidney, liver prostate
methylarsonic acid (MMA(, dimethylarsonic acid are main carcinogens
decrease prot and nutrient nutrients-->incr MMD and DMA
Fe, Zn, B3, choline, methionine, seleiumn
LOOK UP http://www.ncbi.nlm.nih.gov/pubmed/16140620
methylation is phase II proces but methylation products increased cancer
Dietary intake and arsenic methylation in a U.S. population.
Steinmaus C, Carrigan K, Kalman D, Atallah R, Yuan Y, Smith AH.
Source
Arsenic Health Effects Research Program, School of Public Health, University of California, Berkeley, CA 094720, USA.
Abstract
Millions of people worldwide are exposed to arsenic-contaminated drinking water, and ingestion of inorganic arsenic (InAs) has been associated with increased risks of cancer. The primary metabolic pathway of ingested InAs is methylation to monomethyl arsenic (MMA) and dimethyl arsenic (DMA). However, people vary greatly in the degree to which they methylate InAs, and recent evidence suggests that those who excrete high proportions of ingested arsenic as MMA are more susceptible than others to arsenic-caused cancer. To date, little is known about the factors that determine interindividual differences in arsenic methylation. In this study, we assessed the effect of diet on arsenic metabolism by measuring dietary intakes and urinary arsenic methylation patterns in 87 subjects from two arsenic-exposed regions in the western United States. Subjects in the lower quartile of protein intake excreted a higher proportion of ingested InAs as MMA (14.6 vs. 11.6%; p = 0.01) and a lower proportion as DMA (72.3 vs. 77.0%; p = 0.01) than did subjects in the upper quartile of protein intake. Subjects in the lower quartile of iron, zinc, and niacin intake also had higher urinary percent MMA and lower percent DMA levels than did subjects with higher intakes of these nutrients. These associations were also seen in multivariate regression analyses adjusted for age, sex, smoking, and total urinary arsenic. Given the previously reported links between high percent MMA and increased cancer risks, these findings are consistent with the theory that people with diets deficient in protein and other nutrients are more susceptible than others to arsenic-caused cancer.
PMID: 16140620 [PubMed - indexed for MEDLINE] PMCID: PMC1280394
ARSENIC CAUTIONS
do not burn txd wood
test soil before planting garden
TESTING
urine best, hair is OK
CBC and CMP to look at HCT and liver fx
EKG
derm and neuro exam
LEAD
Pb, heavy soft metal
"plumb"ing
USES: batteries #1, ammo #2, solder for pipes, plumbing, cans, fishing (sinkers)
glass, ceramics, paints, pigments, glazes, cosmetics, hair dye, gasoline
Chart: decrease in lead use in gas strongly correlated with decrease in blood lead in US
Peak lead in gas and blood: 1976, decreasing to 1992
Lead in pain increases drying, durability, corrosion prevention, white house paint before 1955 was 50% Pb, beginning 2010 all contractors and renovators must be certified in lead assessment and removal
Standards: 10ug/dl kids, 25ug/kL adults is upper limit acceptable
HEALTH EFFECTS OF LEAD
neuro, hematological are main systems
changes enzymes, stored in bone and bums, sudden osteoclastic activity can increase serum lead
demyelination, inhibits GABA release, reduces neural formation/growth
SX
fatigue, lassitude, insomnia
mm weakness, paresthesia, neurasthenia, seizures, coma, death
decreased cognitive performance is an early sign, delayed development, learning disabilities, reduction in motor skills, emot, soc, attention, ADHD, ASD, anti-social behaviors
*countries with highest lead levels also have highest murder/crime rates!! (study 2-3 yrs ago)
*incarcerated peeps have higher levels than regular pop
16% of kids in US have toxic lead levels (NHANES datae) dt exposure to pain
kids have 50% gastric absorption of Pb, 10% in adults
kids susceptible dt incr rate of neural development
lower SES pops have more exposure to lead, race also linked
(blacks most, hispanics next, caucasians least exposure) (SES = socioeconomic status)
HEALTH EFFECTS OF LEAD
hypochromic anemia (heme production reduced dt alpha aminolevulinate dehydratase (ALA) inhib
iron doesn't get into porphyrin ring, inhibited at 2 steps
hemolytic anemia, acute exposure toxic to formed RBCs
mild hypertensive effect (2-3mm Hg)
lowered HR variability (neuro effect on ANS nerves)
abd cramping, pain, decr absorption of calcium (+2 state)
no science yet on systemic vitamin D effects but suggestion is that Pb inhibits production of D
immune, CVD, cancer, mood effects? Maybe.
PTH mediated absorption of Pb in GI, also resorption and retention in kidney
Pb augments PTH function in osteoblasts
Pb inhibits PTH induced maturation of chondrocytes
directly nephrotoxic, exacerbated by HTN, NIDDM, (cadmium also nephrotoxic)
Fanconi syndrome = failure of prox tubules to reabsorb electrolytes, glucose, phosphates
"saturnine" gout = hyperuricemia from damaged proximal tubules
decreases sperm count, motility, morphology
decreases female fert, incr miscarriage, premie birth
crosses placenta, affects neuro development
most organic lead exposure is dt high performance fuel, race car drivers, auto-mechanics
Sx: irrit, anx, restless, mania, depression
LEAD TESTING
Urine is usual way to check: chelation, ALA, coproporphyrin
Blood levels: 10ug/dl kids, 25 adults
CBC: micro-hypo anemia, basophilic stippling
erythrocyte protoporphyrin (EP) is precursor to heme
EP elevated if Pb >35ug/dl, not sensitive or specific
X-ray for lead lines in bones
PE for Burton's line, pale blue on gingiva
HAIR analysis not valid dt air contamination?
FREE testing in PDX: Josiah Hill clinic, free, monthly
Kimia Ueoka 503-eight oh two-7389 Kimie at jhillclinic dot org
http://www.jhillclinic.org/programs/#bloodtest
MULTNOMAH cty testing for peds under 6 503-988-3828, www.co.multnomah.or.us/health/immunizations
lead interferes with nutrients, iron, ca, zinc
zinc inhibits absorption of Pb
Leadline 503-988-4000
free home water testing
portlandonline.com/water/index.cfm?&c=29587
COSMETICS
makeup, hair products, lip balm, sun block, tanning oil
lotion, moisturizer, perfumes, deodorants
may contain toxic metals, VOCs (formaldehyde, benzene)
plastics (BPA, phthalates), preservatives (parabens)
use of makeup @ puberty, rite of passage, just entering hormonal growth stage
http://www.ewg.org/reports/teens
web: The story of cosmetics safecosmetics.org/index
suncreen concerns on ewg, shopper's guide on ewg
MERCURY
Hg, atomic #80, quicksilver
3 forms: metallic, inorganic (salts: HgCl calmonel, HsS cinnabar)
and organic (methyl and ethyl mercury)
HAIR TESTING VALID because of affinity to sulphur
can get historical levels from museum specimens to eval environmental levels
Human exposure: #1 source is coal combustion
#1 natural source: volcanic deposits and vapours
accumulation in aquatic ecosystems, fish have natural adaptation to store Hg s harm
metallothionines
uses: thermostats, electrodes, lighting (neon, fluorescents), thermal conduction (thermometers, none after 2003 in OR), cosmetics (mascara, blush), insecticides, fungicides, herbicides, medicine
amalgam fillings (50%), thimerosal preservative in vaccines, orig use to tx syphillis
gastric absorption very low, most absorption via inhalation/mucosal absorption of vapour
# of mercury fillings correlates direction to person's mercury concentration
serum mercury drops immediately after removal of amalgams
Tim Chapman is local dentist who removes amalgams, doesn't use mercury
ELEMENTAL MERCURY IN LIGHT BULBS
Hg is activator in fluorescent and neon lighting
500mg in thermometer, 0-100mg in bulb, CFL 0-50mg, neon 250-600mg in 100% of bulbs
CFL - compact fluorescent bulb
no studies on health risk of broken bulbs
broken bulb: open windows, leave area, wait until gas disperses, clean up glass and dust
http://www.epa.gov/cfl/cflcleanup.html
RECYCLE bulbs at IKEA and Home depot (free!)
**and I wanted a neon light that says "walkins welcome" to light up whenever I'm not booked up
SX OF ELEMENTAL MERCURY
dizzy, fatigue, alssitude
confusion, impatience, irrit
erethism: shyness and blushing, emotional and vasomotor instability
Hatter's dz: felt maker, movie presentation as psychosis not related to real mercury toxicity
INORGANIC MERCURY
absorbed in GI and by skin
was in calomel used for poison ivy
doesn't cross BBB
Sx: GI and renal: SLUDGE, erosion of gingiva, teeth, oral mucosa, metallic taste
stomatitis, gastritis, neprhotoxic, tubular necrosis
Pink dz, red hands and feet palms
leg cramps, irrit, erythem, photophobia
THIMEROSAL IS ORGANIC
derived from/metabolized to ethylmercuy (C2H3Hg)+
antifungal, antiseptic, preservative
also in eye washes, contat lense solutoins, nasal sprays
used since 1930's
single Hg dose per vaccines approx 12.5ug
ORGANIC MERCURY
best absorbed
easily crosses BBB, resembles methionine (Ch3Hg+cysteine)
bacteria methylate mercury then it bioaccumulates in the food chain
Minimata Bay, Japan 1956, first concern of aqautic Hg pollution
industrial dumping-->10,000 ill, neuro sx and birth defects
SX: NEURO; parestheia, lassitude, irrit, confus, mood swing, confus, hallucination, delirium, insomnia, mania, erethism (shy/bashful) coma
renal toxicity
WORST FISH: swordfish, shart, tuna, salmon/farm/atlantic, grouper, sea bass, halibut
BETTER: mackerel, sardines, shrimp, trout, wild salmon, light tuna
www.edf.org/page.cfm?tagID=1521
limit to 1 can of tuna/week
MERCURY TESTING
whole blood best for acutes
urine: 24hr best for chronic, chelation
hair analysis OK for methyl mercury only, will not show elemental (amalgams)
SX OF ORGANIC MERCURY
renal, immune and neuro effects
neurodegeneration, neurofibrils denuded in 20 minutes
cytotoxic to renal tubules
immunosuppression, AI in mice
parestheias, ataxia, dysarthria
sensory disturbance (visual, auditory)
N/V/D
MERCURY AND AUTISM
correlation with autism? 1/100 now vs 1/10,000 in 1960, 5% of kids now autistic
healthandenvironment.org/autism
autism-society
problem with thimerosal hypothesis: vaccination rates have decrased, thimerosal removed from most vaccines since 2001 but autism rates continue to increase
still in some flu vaccines incl H1N1, multi-use vials
Hannah Poling March 2008 rare mito dz dt Hg vaccine injury, awarded $1.5 million
CDC/AAP STUDY 2010 shows no link but was this an honest study?????
DECLINE IN AUTIMS RATES IN dENMARK CONINCIDED WITH REMOVAL OF THIMEROSAL
this info purposefully left out of 2003 CDC report
www.sacbee.com/2011/10/25/4005040/scandal-exposed-in-major-study.html
this after Dr Thorsen indicted for $11mil in embezzlement and fraud from CDC
CADMIUM
Cd, atomic #48
bluish white metal
usu +2 state
USES: in batteries (ni-cd), pigments, paints, galvanizing, electroplating, nuclear reactors, PVC stabilizers, fertilizers
EXPOSURES: batteries, galanized metal (pipes, old ice trays), soil/groundwater dt fertilizer, food and water: shellfish, organ meats, leafy greens, potatoes, grains, peanuts, soybeans, sunflower seeds
tobacco is #1, 1-3ug Cd/day per pack
smokers have 4-5x more than nonsmokers, not so much from 2nd hand smoke
industrial
cadmium in McD's Shrek glasses, 12 million glasses recalled, red/orange paint
CADMIUM ACUTE SX
inhalation-->bronchitis, dyspnea, pneumonitis, edema, anosmia
metal fume fever: flu sx, burning chest pain, metallic taste in mouth
competes with Zn, Cu, Se, Fe, Ca (+2 ox state)
subs in bone (Ca), enzymes (Zn, immune), receptors (Ca-->HTN)
stored in kidneys, liver, lungs, bones
CHRONIC
renal failure, metallothionine-->renal lysosomes
GI: genital cancer, prost, test, infert, teratogen
osteomalacia, porosis
lung ca
HTN
BAD NEWS
flaxseed incr cadmium retention
ncbi.nlm.nih.gov/pubmed/20876162
GOOD NEWS
vit C reduces/prevents Cd induced vasc dysfx, HTN, and ox stress
pubmed/20872....
TESTING
urine best 24 hrs avg 1ug/gcreat
blood for acute
hair: no correlation with body burden
urinary retinol binding prog is nonspecfic test
CHROMIUM
Cr, atomic #24
steel gray hard metal, resists corrosion
3 forms: elemental Cr, Cr3+, Cr6+
very different, 3+ is essential glucose tolerance factor, 6+ is toxic
common in mining, metal manufacturing, stainless, chrome plating
paints, many colors, leather tanning, wood preservative (CCA with arsenic)
CROMIUM 6 TOXIC FORM
Erin Brockovich story
ingest-->GI irrit, ulcer, anemia
inhale-->irrit, bronch, CA
male-->sterile
extreme oxidative damage: kidneys, liver, vasculature
derm-->ulcer (painless), inflam "chrome holes"
highly oxidative
TESTING: urin, serum, hair is valid
Treat: antiox, vit C, E, flavinoids, GSH, ALA, CoQ10
ALUMINUM
Al, atomic #13
lightest metal there is, soft, malleable
found in: bauxite, easy to recycle, hard to extract
used in cans, pots, siding, foil
medical: antacides, astringents, aspirin, antiperspirants mc
EXPOSURES: in food from soil, inhalation, leaches from cookware, in personal care
10/4/10 toxic red sludge in Hungary, big damage
HEALTH EFFECTS: NOT AS TOXIC but still irrit resp
kidneys accumulate Al when sick
est related gene expression
antiperspirant use linked to breast ca, stagnation of local lymphatics
ALZHEIMERS? there's an association but is there causality?