Heavy Metals Gillian Beauchamp, MD

Mystery Case 1 4 year old boy Previously healthy except for recurrent OM 1 month of irritability – parents describe him as ‘withdrawn’ Night sweats for several weeks The patient will not walk – states ‘my legs hurt’ No other illnesses Normal oral intake and weight gain Vaccines up to date No travel or pets Moved into a freshly painted home 3 months ago

Exam General: diaphoretic and crying Afebrile with vital signs within normal limits Nose, fingers and toes are erythematous and peeling but no tenderness to palpation medicalassessmentonline.com

Quiz What is the differential diagnosis for this patient? What testing would you like to order?

Differential Diagnosis Erythematous rash of extremities Staph or strep skin infection Kawasaki disease Boric acid exposure Mercury toxicity Stevens-Johnson/TEN Fifth disease Scarlet fever Rubella Drug rash Irritable and withdrawn patient Child abuse Cognitive delay Autism spectrum Possible fever, diaphoresis, and painful extremities Acute rheumatic fever Hematologic illness Kawasaki – no mucosal involvement; no conjunctivitis Boric acid poisoning – erythema and peeling of skin – but no GI sx in this patient makes this less likely No exposure to drugs/antibiotics No other recent illness such as strep throat (acute rheumatic fever); measles (no Koplik spots; no cough; no conjunctivitis’ no coryza)

What tests would you like to order? CBC ESR or CRP Metabolic profile X rays of tender lower extremities ASO: streptococcal antibody titers 24 hour urine mercury

Summary of Mystery Case 1 4 year old previously healthy male 3 months of irritability and withdrawn behavior Erythematous, peeling rash over distal extremities Symptoms started after moving into a newly painted home.

Work up CBC normal Metabolic profile normal Urinalysis normal 24 hour urine mercury 324 ug/L – (normal is < 20 ug/L) Background urine conc of 20 ug/L is established for adults; unknown for pediatric patients

Mystery Case 2: The Same Toxin! 8 patients present to the emergency department 15 kg of liquid metal spilled from a barrel that was accidentally punctured by a forklift at a battery manufacturing plant This occurred in a 10 m2 workspace The workers attempted to clean the spill prior to notifying the floor supervisor – exposure time was 15 minutes All patients complain of cough and difficulty breathing 6 patients complain of headache 3 patients complain of nausea and vomiting 2 patients state they have a metallic taste in their mouths Mercury spill – 6 pounds at a battery manufacturing plant – spill from a drum that was accidentally punctured by a fork lift.

Quiz What toxic exposure do you suspect? Is decontamination needed to protect emergency department staff? What tests do you want to order? Is any treatment necessary?

What toxic exposure do you suspect? Elemental mercury exposure

Is decontamination needed? Elemental mercury vapors can cause toxicity Remove and bag clothing Wash skin of patients Dermal absorption of elemental mercury is minimal Proper removal of mercury must be performed at the work site Spill may be covered with powdered sulfur (Merc-X), bagged and discarded Polymer-based decontamination gel can be used to adhere to, and remove mercury Open windows in space -indoor spill of metallic mercury: cover spill with powdered sulfur and discard and contaminated material -spills can result from thermometer or compact fluorescent light: use self-contained vacuum systems -Decon-gel (polymer based - used to cover mercury - picks mercury up on its sticky surface), mercury vacuums, merc-x (sulfide based product that coats the mercury beads and alters structure) -lightbulb spill at home: duct tape to pick up pieces; double bag and open windows  EPA response team in US will use a mercury vapor analyzer to determine mercury vapor concentrations. The Agency for Toxic Substances and Disease Registry recommends clean up, ventilation + removal of any mercury-contaminated items such as furniture, carpet, clothing, if concentration greater than 1 ug/m3; evacuation if over 10 ug/m3. In this type of exposure, conc can be over 600 ug/m3.

What tests do you want to order? Chest X-ray Interstitial pneumonitis Pulmonary edema Renal function and electrolytes Blood mercury concentration > 5 ug/L + symptoms warrants treatment 24 hour urine mercury concentration Non-metal, plastic container 20 ug/L is adult background concentration 20-200 ug/L – tremor 200-500 ug/L – irritability, memory loss, kidney injury 500-1000 ug/L – gingivitis, CNS disturbances Hair testing is not useful clinically. However, hair testing has been performed to assess maternal hair for estimate of fetal MeHg exposure.

Test Results CXR: with mild pulmonary edema Observation overnight until symptoms improve Building mercury concentration 673 ug/m3 HAZMAT team disposes of mercury and opens area for 24 hours Blood mercury: 134 ug/L and 215 ug/L Results for the two individuals involved in clean up after exposure

Is any treatment needed? 6 patients had improvement in their symptoms in the ED Discharge home with PCP follow up for urine mercury every 2 weeks until below 20 ug/L 2 patients remained symptomatic Admitted for repeat CXR in am IVF overnight for fluid losses due to GI effects Hemodynamic monitoring Discharge home when asymptomatic Chelation with dimercaptosuccinic acid: DMSA

Chelation Oral Succimer (DMSA) DMPS – available outside US Pediatric: 350 mg/m2 TID X 5 days, then 350 mg/m2 BID for 14 days Adults: 10 mg/kg TID for 5 days, then 10 mg/kg BID for 14 d Can repeat courses but recommend 2 weeks between courses Available in 100mg bead-filled capsules DMPS – available outside US IM BAL if unable to tolerate oral intake (cannot use for organic mercury due to increased brain uptake 4 mg/kg deep IM injection -peds: 350 mg/m2 TID X 5 days, then 350 mg/m2 BID for 14 days -adults: 10 mg/kg TID for 5 days, then 10 mg/kg BID for 14 d -can repeat courses but recommend 2 weeks between courses -available in 100mg bead-filled capsules -rebound after treatment: 60% drop over 5 days, then stays stable until DMSA stopped, then rebound after treatment to 20-40% lower than pre-DMSA level -BAL cannot be used for organic mercury exposure because it increases conc of MeHg in the brain – however, ok to treat phenylmercury poisoning because phenylmercury is rapidly oxidized to Hg2+ in the body and therefore acts mre like inorganic mercury There is no antidote for organic mercury exposure – supportive care

What do these patients have in common? House Paint ‘Quicksilver’ 4 year old boy 1 month of irritability – parents describe him as ‘withdrawn’ Night sweats for several weeks Pain in legs Moved into a freshly painted home 3 months ago 8 patients 15 kg of liquid metal Cough and difficulty breathing Headache Nausea and vomiting Metallic taste in their mouths

Mercury Toxicity Elemental Organic Inorganic A metal found in the environment – off-gassing from soil and water Silver liquid at room temperature – vaporizes easily Accounts for most occupational exposures – thermometers, switches/gauges, batteries Dental amalgams Folk remedies, cosmetics, pharmaceutical preservatives Organic Mercury in environment is methylated by microorganisms in soil and water MeHg accumulates in aquatic organisms in food chain Organomercury compounds used as fungicides and bacteriocides in paint Inorganic Mercury salts Hg1+ and Hg2+ Industrial processes that produce mercury containing effluents: chlorine and caustic soda production; mining, ore processing, metallurgy, electroplating, chemical manufacturing, ink manufacturing, paper milling, leather tanning, textile manufacturing and pharmaceutical production. In US, food sold for dietary consumption cannot have more than 1 ppm of mercury -In US, interior and exterior latex paints contained organomercury compounds such as phenylmercury acetate – child in Michigan, US with acrodynia in 1989 from living in home painted with such paint. EPA recommended discontinuation of mercury use in indoor paints in 1990 and in exterior pain in 1991. Since partially used cans are kept for re-painting, and because not all countries regulate use of mercury in paints, exposures may continue. -Mercurials have been used for cathartics, diuretics, antisyphilitics, antiseptics, antipruritics, anti-inflammatories, antiparasitics. -Latin and Carribean cultures: folk remedies for GI illness and in occult practices -Perservatives in eye drops, ointments, nasal sprays, vaccines -Amalgam use: under 1% of daily mercury vapor dose that is considered safex

Mercury: Patients at Risk Industry Science & Healthcare Chlorine production Caustic soda production Electroplating Explosives manufacturers Felt makers Leather tanners Ink manufacturers Battery, lamp and switch manufacturers Miners: Au, Ag, Cu, Zn, HgS Painters Laboratory personnel Dental personnel Pharmaceutical producers HgS = cinnabar

Elemental Mercury Children are often exposed due to curiosity about elemental mercury Industrial workers are at risk for inhalational exposure 80% absorbed when inhaled Minimal absorption with ingestion Half life is 60 days Recall our battery factory workers who presented with cough, dyspnea, nausea, vomiting and metallic taste in the mouth – later, interstitial pneumonitis and pulmonary edema. Dermatitis can also occur with dermal exposure The World Health Organization aims to phase out the use of mercury in medical devices by the year 2020

Organic Mercury Fetuses, infants and children at increased risk Readily crosses placenta and concentrates in breast milk 1950s: Minamata Bay – 41 deaths and 30 cases of permanent pediatric neurological sequelae Organomercury compounds used as bacteriocides and fungicides in paint

Inorganic Mercury Historically used in teething powders, skin-lightening ointments and laxatives Dermal absorption can result in acrodynia Oral ingestion of 1-4 grams can be lethal Severe GI symptoms leading to cardiovascular collapse and shock Delayed death can also occur due to ATN leading to renal failure and uremia Half life is 40 days Inorganic mercury ingestion can be treated with lavage or catharsis, however, care must be taken to prevent dehydration due to large volume loss Treat with chelation

Pathophysiology of Mercury Poisoning Mercury alters the structure and function of proteins (enzymes) by binding to sulfhydryl groups

Mercury Neurotoxicity Occur with elemental mercury vapor and organic mercury exposure Shyness, irritability and loss of developmental milestones in children Tremor, distal paresthesias, motor & sensory nerve conduction delay Children born to mothers with high oral mercury from fish ingestion Cognitive delay Ataxia Deafness Constricted visual fields & blindness Cerebral palsy

Mercury Respiratory Toxicity With acute elemental mercury inhalation

Mercury Gastrointestinal Effects Acute inhalational elemental mercury exposure can result in GI losses and shock Ingestion of inorganic mercury salts can result in gastritis with necrotizing ulceration of the intestinal mucosa

Mercury Nephrotoxicity Occurs with ingestion of inorganic mercury salts Nephrotic syndrome Proteinuria Acute tubular necrosis with resultant renal failure

Standards & Regulations EPA industrial emissions regulations: 2300 g/24 h WHO: mercury in drinking water max 1 ppb (1 ug/L) EPA drinking water max is 2 ppb FDA: 1 ppm in fish (average is 0.2 ppb) & 2 ppb in bottled water The occupational threshold limit value (TLV) has been lowered to 50 mcg/m3 or less in most countries - confirmed The Federal Occupational Health and Safety Administration (OSHA) in the United States has set a mercury permissible exposure limit (PEL) of 100 mcg/m3 (eight-hour time-weighted average [TWA]), but some state OSHA programs regulate a stricter limit at 50 mcg/m3 (eight-hour TWA) - confirmed Exposure to mercury has significantly lessened during the last few years because of increased attention to minimizing exposure. In dentistry, for example, ambient mercury concentrations between 1960 and 1970 were frequently approximately 25 mcg/m3; present values are below 5 mcg/m3 due to improved ventilation and handling of amalgam.   Previously, mercury miners and chloralkali industrial workers commonly encountered air concentrations of mercury in excess of 100 mcg/m3 [40]. Clinically significant health effects including neuropsychological abnormalities, pulmonary toxicity, and renal dysfunction were common at such exposures [41,42]. The occupational threshold limit value (TLV) has been lowered to 50 mcg/m3 or less in most countries. The Federal Occupational Health and Safety Administration (OSHA) in the United States has set a mercury permissible exposure limit (PEL) of 100 mcg/m3 (eight-hour time-weighted average [TWA]), but some state OSHA programs regulate a stricter limit at 50 mcg/m3 (eight-hour TWA) (United States Department of Labor Occupational Safety & Health Administration. Mercury. https://www.osha.gov/SLTC/mercury/standards.html (Accessed on May 22, 2015).

Back to Mystery Case 1: Acrodynia Exposure to elemental mercury, mercury salts or phenylmercury Leg cramps Irritability and shyness Painful erythematous and peeling digits and nose Lookfordiagnosis.com

Back to Mystery Case 2 Acute inhalational exposure to elemental mercury Dyspnea, cough  pulmonary edema and pneumonitis GI symptoms  shock and renal failure

Match the following mercury exposures to the clinical syndrome Quiz Match the following mercury exposures to the clinical syndrome Exposure Clinical Syndrome Elemental mercury vapor Inorganic mercury dermal exposure Fetal organic mercury exposure through excessive maternal predator fish consumption Blindness, deafness, cognitive delay & ataxia Dyspnea, cough, nausea, metallic taste in mouth Acrodynia: erythematous, peeling fingers, toes and nose, shyness & irritability

Match the following mercury exposures to the clinical syndrome Quiz Match the following mercury exposures to the clinical syndrome Exposure Clinical Syndrome Elemental mercury vapor Inorganic mercury dermal exposure Fetal organic mercury exposure through excessive maternal predator fish consumption Blindness, deafness, cognitive delay & ataxia Dyspnea, cough, nausea, metallic taste in mouth Acrodynia: erythematous, peeling fingers, toes and nose, shyness & irritability

Match the following mercury exposures to the clinical syndrome Quiz Match the following mercury exposures to the clinical syndrome Exposure Clinical Syndrome Elemental mercury vapor Inorganic mercury dermal exposure Fetal organic mercury exposure through excessive maternal predator fish consumption Blindness, deafness, cognitive delay & ataxia Dyspnea, cough, nausea, metallic taste in mouth Acrodynia: erythematous, peeling fingers, toes and nose, shyness & irritability

Match the following mercury exposures to the clinical syndrome Quiz Match the following mercury exposures to the clinical syndrome Exposure Clinical Syndrome Elemental mercury vapor Inorganic mercury dermal exposure Fetal organic mercury exposure through excessive maternal predator fish consumption Blindness, deafness, cognitive delay & ataxia Dyspnea, cough, nausea, metallic taste in mouth Acrodynia: erythematous, peeling fingers, toes and nose, shyness & irritability

Match the following mercury exposures to the clinical syndrome Quiz Match the following mercury exposures to the clinical syndrome Exposure Clinical Syndrome Elemental mercury vapor Inorganic mercury dermal exposure Fetal organic mercury exposure through excessive maternal predator fish consumption Blindness, deafness, cognitive delay & ataxia Dyspnea, cough, nausea, metallic taste in mouth Acrodynia: erythematous, peeling fingers, toes and nose, shyness & irritability

Match the following mercury exposures to the clinical syndrome Quiz Match the following mercury exposures to the clinical syndrome Exposure Clinical Syndrome Elemental mercury vapor Inorganic mercury dermal exposure Fetal organic mercury exposure through excessive maternal predator fish consumption Blindness, deafness, cognitive delay & ataxia Dyspnea, cough, nausea, metallic taste in mouth Acrodynia: erythematous, peeling fingers, toes and nose, shyness & irritability

Match the following mercury exposures to the clinical syndrome Quiz Match the following mercury exposures to the clinical syndrome Exposure Clinical Syndrome Elemental mercury vapor Inorganic mercury dermal exposure Fetal organic mercury exposure through excessive maternal predator fish consumption Blindness, deafness, cognitive delay & ataxia Dyspnea, cough, nausea, metallic taste in mouth Acrodynia: erythematous, peeling fingers, toes and nose, shyness & irritability

Questions about Mercury?