Management of People Exposed to Drinking Water with Excessive Heavy Metals Training to PCD 2017

Antimony (Sb): Important sources of human exposure • Significant antimony exposures may occur in an

occupational setting including metal smelting, coal-fired power plants and refuse incineration.

• Antimony compound (at a dosage of 20,000 µg/kg/day) has been used in the treatment of some parasitic infection

• Total exposure from food and drinking-water is relatively very low compared with the conditions above

Sb: guideline values • WHO drinking water guideline value for Antimony: 20 μg/L

• WHO Tolerable daily intake (TDI): 6 μg/kg body weight (360 μg/day for a 60kg person)

Toxicities of Sb after oral exposure

• Oral intake of soluble antimony salts (at the level of 30,000 – 60,000 µg) may exert a strong irritating effect on the gut and trigger sustained vomiting

• Reported toxicities after oral exposure are mainly due to ingestion of soluble Sb3+ salts • Acute

• Mainly gastrointestinal (vomiting, diarrhea, abdominal cramps) • Cardiotoxicity • Similar to Arsenic

• Chronic • Oculotoxicity (optic neuropathy, uveitis, retinal bleeding)

[WHO] [Agency for Toxic Substances and Disease Registry (ATSDR), CDC] Handbook of the Toxicology of Metals, 3rd edition

Toxicities of Sb after oral exposure

• No acute/chronic systemic toxicities after oral exposure to Sb5+ were reported from the literature • For therapeutic exposure to parenteral Sb5+ drugs, acute/subacute and

rarely chronic toxicities (gastrointestinal, cardiovascular, pancreatitis, hepatotoxicity) were reported, usually not severe and reversible

• No reproductive/developmental toxicities were reported after

oral exposure to Sb

• No evidence to indicate carcinogenicity by the oral route

[WHO] [Agency for Toxic Substances and Disease Registry (ATSDR), CDC]

Therapeutic Vs toxic dosages of Sb5+

• WHO guideline water Sb level: 20 ug/L • Recommended therapeutic dose of Sb5+

• 20 mg/kg/day with no upper limit [Am J Trop Med Hyg.1992 Mar;46(3):296-306.][WHO]

• By IM or IV injection • For a average 50-kg person therapeutic dose = 1 g/day Even if the water Sb level is 10x the WHO recommended control

level (200 ug/L) one has to drink 50,000 L of water to be equivalent to that for therapeutic use (assuming all Sb5+ can be absorbed after ingestion)

Cadmium (Cd) • No known biological role for Cd or its salts

• Undetectable at birth • Bioaccumulation appears to be a by-product of increasing

industrialization

• Major sources:

• From non-ferrous metal mining and refining, manufacture and application of phosphate fertilizers, fossil fuel combustion, waste incineration and disposal

• Under non-occupational settings, food is the main source of exposure to cadmium. According to WHO, dietary daily intake of individuals ranges from 10 to 35 μg.

• Smoking will increase the intake of cadmium

Cd: guideline values

• WHO drinking water guideline value for Cadmium: 3 μg/L

• WHO Provisional tolerable monthly intake (PTMI) = 25 μg/kg body weight (equivalent to about 50 μg/day for a 60kg person)

Cadmium toxicities after oral exposure • Acute excessive ingestion, mainly gastrointestinal (GI) effect:

– Lethal oral dose: 350-3500 mg • A dose of 3 mg Cd (i.e. 1000 L water at WHO Cd cutoff or 100 L at 10x

WHO Cd cutoff) has no acute effects on adults (Krajnc et al., 1987) – GI effects: Nausea, vomiting, diarrhea, abdominal pain, tenesmus – Rarely: hemorrhagic gastroenteritis, liver and kidney necrosis, cardiomyopathy,

metabolic acidosis

• Chronic toxicities, mainly renal effect: – Renal: Progressive renal tubular dysfunction, proteinuria, nephrolithiasis

• Chronic intake 140 - 255 ug Cd per day (drink 2 litres of water per day at 20x – 40x of WHO Cd guideline value) associated with low molecular weight proteinuria in elderly (JECFA, 1989)

– Musculoskeletal: Bone lesions secondary to Cd-induced renal damage and cadmium accumulates in bone

• pseudofracture, osteomalacia, osteoporosis

• Chronic toxicities (con’t): – Carcinogenicity: IARC as group 1 carcinogen

• Carcinogenicity well demonstrated in experimental animals, less conclusive in humans (other than strongest evidence with inhalational exposure in occupational setting and lung cancer)

– Specific groups:

• Pregnancy: inconsistent evidence about its effect on pregnancy, may increase incidence of preterm delivery; anyway, not known to be teratogenic

• Lactating: small amount will enter breast milk (5-10% of level in blood)

• Children: Similar health effect as adult, no definite harmful effects on child development or behavior have been reported.

Cadmium toxicities after oral exposure

Chromium (Cr) Trivalent form (Cr3+) Hexavalent form (Cr6+)

• Essential trace element important in glucose metabolism

• Deficiency associated with diabetes and atherosclerosis

• Form of Cr given as IV/oral supplement if indicated

• Little evidence that Cr3+ is toxic or carcinogenicity to human

• IARC: Not classifiable as carcinogen in human

• High oxidative potential at point of entrance, causes damage to cellular constituents, hence considered genotoxic, cytotoxic and carcinogenic

• Toxicological importance in inhalational occupational exposure with major risk of carcinogenesis e.g. bronchogenic/ nasal

• IARC: Known human carcinogen by inhalation route only

[Tietz. 5e] [Goldfrank 10e]

Chromium: oral exposure

• Water • Leaching from distribution system in both Cr3+ and Cr6+

[Shock et al., 2008]

• Food - Present in meat, fish, fruit, vegetable

• All present as Cr3+ unless contaminated by local source [Sanexen, 2009]

• Under non-occupational settings, food remains the major source of chromium intake. WHO report indicated that food contributes 93–98% of the total intake of chromium while 1.9–7% from water.

[Chromium in Drinking-water, WHO 2003] [Goldfrank. 10e][Tietz. 5e]

Cr: guideline value • WHO drinking water provisional guideline value for

Chromium: 50 μg/L

Chronic dietary exposure to Cr6+

• Carcinogenesis

• Limited data on carcinogenesis from oral exposure in human

• Increase GI tract neoplasms on chronic oral exposure in animal study

• Adverse effects of using of water with exceedingly high Cr6+ level has once been reported in China [Zhang and Li, 1987] • [Cr6+] in drinking water 20,000 µg/L (400X WHO cutoff for total Cr)

• 155 subjects developed sores in the mouth, diarrhea, stomachache, indigestion, vomiting, elevated white blood cell counts with respect to controls, and a higher per capita rate of cancers, including lung cancer and stomach cancer

• Note: Precise exposure concentrations, exposure durations, and confounding factors were not discussed

[WHO] [Agency for Toxic Substances and Disease Registry (ATSDR), CDC]

Chronic dietary exposure to Cr6+

• Non-cancer effects • Reproductive/ Developmental

• Limited reports in human (by ingestion route) • Decrease sperm count, increase % abnormal sperm observed in

animals (≥5200 µg/kg/day) • Post-implantation loss, decreased fetal weight, internal and skeletal

malformation in animals (≥ 35,000 µg/kg/day)

• Others (with much higher level of exposure) • Haematological (microcytic, hypochromic anaemia) • Mild to moderate elevation in hepatic aminotransferases and

abnormal liver architecture • Transient elevation in urinary ß-microglobulin

[WHO] [Agency for Toxic Substances and Disease Registry (ATSDR), CDC]

Cu: Common Sources • Copper is an essential element that has regulated GI

absorption

• Food is the most common source. Dietary copper intakes for adults range from 1 to 3 mg/day in some studies.

• Copper is an essential trace element.

• Drinking water contributes 0.1–1 mg/day in most situations.

• Use of vitamin/mineral supplement will increase exposure by up to 2 mg/day

Cu: guideline value

• WHO drinking water guideline value for Copper: 2 mg/L

• WHO upper safe limit for copper consumption is estimated to be 10 mg/day

Toxicities of Cu after oral exposure • Acute

• GI irritation (at 4-8 mg/L) with rapid onset vomiting, abdominal pain and less commonly GI bleeding or even perforation. Metallic taste and retrosternal chest pain.

• Rapid haemolysis following methaemoglobinaemia • Systemic effects include hepatotoxicity, renal and lung toxicities

occasionally. • Most severe cases may lead to shock, CNS depression and sepsis.

• Chronic

• Implication in pathogenesis of neurodegenerative diseases e.g. Alzheimer and Parkinson

Cu: Sensitive Population • Children and infants, especially with infant formula

reconstituted with tap water • higher absorption and lower excretion

• Genetic defects in copper metabolism:

• Wilson disease (prevalence 1 in 5400 in Hong Kong [Mak]) • Restriction of dietary copper alone cannot influence the

progression of the disease [WHO] • Chelation: d-penicillamine, trientine • Liver transplant improves CNS symptoms

Nickel (Ni): Common Sources • Food is the dominant source of nickel exposure in the non-

smoking, non-occupationally exposed population • Oatmeal, dried beans, leaching from nickel containing food

processor

• Water is generally a minor contributor to the total daily oral intake of nickel

Ni: guideline values • WHO drinking water guideline value for Nickel: 70 μg/L

• WHO Tolerable daily intake (TDI) = 12 μg/kg body weight (720 μg/day for a 60kg person)

Toxicities of Ni ingestion

• Dermatological • Eczematous flare-up reactions in skin (Ni-sensitive individuals) • Generalised dermatitis in a 2 year-old boy swallowed two coins

• Carcinogenicity

• Nickel compounds (e.g., Ni oxides, sulphides) are classified as class I carcinogen; metallic nickel are 2B (possibly carcinogenic to humans)

• Inhaled nickel compounds are carcinogenic to humans but there is a lack of evidence of a similar risk from oral ingestion of nickel

Summary • The WHO defined drinking water limits for the five metals

are stringent and substantially lower than the levels causing clinical poisoning

• Universal screening for these metals in blood and urine samples for subjects exposed to drinking water with mildly elevated levels will not be helpful in identifying poisoning

• Such practice is not seen in the rest of the world

• Reduction of exposure by avoidance of such water is the primary measure in clinical management