# Presentation: 138348

## Exposures & Health Effects of Mercury for Humans

- Board of Scientific Counselors
- February 23, 2005

- Rita Schoeny, Ph.D.
- Senior Science Advisor, Office of Water
- U.S. Environmental Protection Agency
- schoeny.rita@epa.gov

## Geochemical Cycle of Mercury

- Adapted from US Dept. of Interior’s  Report on Hg in the Florida Everglades

- Air Emissions are
- 10- 80 of Water
- Burden!

**Notes:**
Hg in three forms
Elemental 
, oxidized (reactive gaseous), organic

## Elemental mercury (Hg0) vapours:
Dental amalgams for most people 
Occupations (such as artisanal mining and chloralkali plants) for some populations
Use of mercury in religious/cultural practices Other incidents (children playing with mercury)
Spills (broken thermometers, thermostats, etc..)
Methylmercury (MeHg): 
Consumption of fish and marine mammals (certain whales, seals)

- Dental amalgams for most people
- Occupations (such as artisanal mining and chloralkali plants) for some populations
- Use of mercury in religious/cultural practices Other incidents (children playing with mercury)
- Spills (broken thermometers, thermostats, etc..)
- Methylmercury (MeHg):
- Consumption of fish and marine mammals (certain whales, seals)

- Major Exposure Pathways

## Slide 4

## Humans are also exposed to other mercury forms including 

- Inorganic mercury salts, mainly through ingestion
- Low levels in some foods (e.g. wild mushrooms)
- Some traditional Asian medicines:
- Cinnabaris (mercury sulfide)
- Calomelas (mercuric chloride)
- Skin lightening creams Ethylmercury from preservative (thimerosal, ethylmercury thiosalicylate) in some vaccines and other medical products
- Use of thimerosal is being eliminated or significantly reduced in many countries

**Notes:**

Only in multiuse vials

## Elemental Mercury Vapor - Toxicity

- Inhalation is main route of exposure
- Readily crosses blood-brain barrier and placenta
- High exposures can cause death
- Nervous system is primary target of toxicity
- Neurological effects include tremors, insomnia, memory loss, headaches, mood changes
- Also toxic to kidney - In body, Hg0 may be oxidized to inorganic mercury (Hg+2), which accumulates in kidney

**Notes:**
All forms of Hg can cause mort at sufficient dose – Known as toxicant since Roman times.  

Mad Hatters from Hg treated felt

## MeHg data are from humans

- Severe poisoning events occurred in 1960s-70s in Minamata Bay, Japan and in Iraq

**Notes:**
Not necessarily the most toxic form, but generally most exposure to humans and wildlife 
Easily absorbed through GI, probably skin
Food type seems to make no difference in absorption; 95% of ingested MeHg is absorbed
MeHg is distributed throughout the body and easily passes the placenta and blood brain barrier
Half-life in body has been measured to be 35 to 190 days (average = 72 days)  
Associated with protein; accumulates in several tissues (brain, kidney)
Two severe poisoning events in second half of 20th century --  Minamata Bay, Japan and rural Iraq
Methylmercury ingested in food causes a wide range of effects, depending on exposure level
Effects can be seen in children born to asymptomatic mothers

There are 3 large, well conducted epidemiologic studies of children exposed in utero from maternal fish consumption
			Seychelles 
			Faroes
			New Zealand	

Many smaller studies of both adult and in utero exposure.
Effects have been observed in populations including Canadian Cree, Madeira, several populations in the Amazon Valley, Ecuador, French Guiana, Finland, Germany

## MeHg  Health Effects

- Spectrum of effects from adult exposure or during development – mortality through subtle effects on ability to learn
- Developing nervous system is a sensitive target for low dose MeHg exposure
- Evidence from human and animals of adverse effect on developing and adult cardiovascular system
- Animal evidence of immune and reproductive effects
- Mechanism is unknown
- Not likely to be a human carcinogen

**Notes:**
Effects on adults included death, paresthesia, tremors, ataxia, hearing and vision impairment, and balance and speech disturbances
Children born to mothers exposed during pregnancy exhibited 
Cerebral palsy, delayed walking/talking, delayed startle responses and other neurological effects 
Contemporary studies in children exposed in utero
Large studies of populations consuming seafood as well as some smaller studies 
Effects on auditory evoked potential, cardiovascular system and on tests associated with ability to learn and process information 

## Dose Response -- General

**UF**

**Dose**

**         ****Response **

- 0%

- a%

**Environmental**
**Exposure Levels**
**of Interest**

**RfD              LED****a                 ****ED****a****                  **

- Nonlinear Default

**Empirical**
**Range of **
**Observation**

**Range of**
**Extrapolation**

**Linear Default**

**(Lowest 95% Confidence Limit on Dose)**

**x**

**x**

**(Central Estimate)**

**x**

**x**

**x**

**x**

**NOAEL**
**LOAEL**

**x**

**Notes:**
Most risk assessors and regulatory agencies use reference dose (RfD), acceptable daily intake (ADI), tolerable daily intake (TDI), minimal risk level (MRL)
All assume a threshold for effect, presume there is a level with no effect or acceptable effect

This was done for elemental, inorganic (oxidized) and methylmercury

## Three State-of-the-art Studies on Children, in utero Exposure

| Faroes | Seychelles | New Zealand |
| --- | --- | --- |
| Northern Caucasian | African | Multi-ethnic |
| 900 mother child pairs | 700 mother child pairs | 200 mother child pairs |
| Cord blood, maternal hair | Maternal Hair | Maternal hair |
| Pilot whale | Variety of fish (mostly small reef fish) | Shark (fish and chips) |
| Effects in 8 to 10 measures | Authors report  no effects associated with mercury  in kids up to 9 years of age | Effects in “IQ” tests |
| Boston Naming Test,  Continuous Performance Test, Finger Tapping, California Verbal Learning | DDST, McCarthy Scales, Bailey Scales, WISC III
 | DDST, McCarthy Scales, WISC R
 |

**Notes:**
State of the art = large populations, good measures of exposures, accepted measures, measures able to detect subtle changes,  meticulous statistical analyses, extensive scientific review and discussion

* Lots of debate, discussion, publications on why no effects in Seychelles – some of same tests as in both Faroes and NZ.  According to Meyers et al 2003, 
Factors include potential bias in enrolment (but offered participation to all and saw no bias in non-participants)
Hair biomarker is subject to wide variability – may be related to ethnicity
Info on pregnancy, birth and feeding were obtained at 6 months – so may be recall errors
Did not assess nutritional covariates (e.g. Se, PUFA)  -- looking at a new cohort 
May have got different results with different tests (but included a lot of Faroes tests)
Different stat procedures may have given different results (but don’t see any evidence of this)

Tests in Seychelles and NZ were based on earlier experience with Pb; generally considered to be IQ tests.  Faroes

See crib sheet on tests

Biomarkers in Faroes include: Cord blood, Maternal hair at parturition (c. 9 cm),Same, first 2-cm segment,Child hair at 12 months,Child blood and hair, 7 years, Child blood and hair, 14 years

## EPA’s RfD 2001

**RfD = ****0.1********g/kg/day**** **(about 1.1 ppm hair, 5.8 ug/L blood) neuropsychological effects in children exposed *in utero*; considers Faroes, Seychelles, New Zealand data.
- “The test scores are all indications of neuropsychological processes involved with a child’s ability to learn and process information.” (NRC 2001)
- Benchmark dose for methylmercury is a level at which one would expect a doubling of the number of poor performers on these tests (from 5% to 10% of the population)
- In Criteria Document and on IRIS, used Boston Naming Test as example – BMDL = 58 ug mercury / L blood
- No data to support a separate RfD for children
- Uncertainty factor is small – 10; thus there is not much of a margin of exposure between an effect level and the RfD
- No evidence of threshold at Faroese exposure level.

**Notes:**
Review -- Based largely on peer-reviewed NRC report: in addition senior EPA scientist review, informal review by key scientists cited in text, interagency review through CENR, external peer review through IRIS, at public meeting, with opportunity for public comment
Two previous RfDs; 1986, EPA used data from Iraqi adults -- Paresthesia was endpoint; 0.3g/kg bw /day; concern that not protective of developmental effects
1997, EPA used data from Iraqi in utero exposure; 0.1g/kg bw /day. Much debate on this estimate. Used in Mercury Study Report to Congress, (after much review, SAB said that the “...RfD, based on the Iraqi and New Zealand data, should be retained at least until the on-going Faeroe and Seychelles Islands studies have progressed much further and been subjected to the same scrutiny as have the Iraqi data.”
EPA used an uncertainty factor (UF) of 10, based on advice of NRC and peer review panel
UF includes consideration of both uncertainty (what we don’t know) and variability (what we do know or can estimate about how individuals or experimental results differ)
PK variability and uncertainties  = 3
According to analyses in NRC report, a factor of 3 accounts for range of variability about 95% of the population.  This UF is among those considered to be chemical specific or data-based
Pharmacodynamic variability & uncertainty = 3 
This UF is based on consideration of uncertainty, basically a default, but a standard approach. 
Additional concerns not reflected numerically in UF: 
Lack of 2-generation reproductive effects assay
Inability to quantify long term sequelae
Selection of critical effect (concern for observable effects below the BMDL).  The reproducibility of cardiovascular and other effects at very low dose makes this concern more acute

Independent reviewers were Gary Ginsberg, Ph.D. (Chair), Kim N. Dietrich, Ph.D., Bruce A. Fowler, Ph.D. , Martha Keating, MS, Chris Newland, Ph.D.,Pam Shubat, Ph.D. Andrew Smith, SM, Sc.D. 
Canada (FNIHB):               Blood              Hair
Normal Acceptable Range      < 20 ppb         < 6 ppm
Increasing Risk                    20-100 ppb       6-30 ppm
At Risk                                    > 100 ppb        > 30 ppm

USA (EPA):
RfD                                              4.4 ppb          1.1 ppm
					         5.8 ppb*

## Cardio Effects Below RfD ?

- Studies in adults
- Finnish men with hair mercury of 2 ppm or more had 2 times
-    greater risk of myocardial infarction (Salonen et al. 1995; Vertanen, 2005).
- Adult men (Israel and Europe) increased mercury associated with increased risk of myocardial infarction.  MeHg exposure “may diminish the cardio protective effects of fish intake” (Guallar et al. 2002).
- No association between mercury exposure and myocardial infarction in U.S. health professionals [unless dentists are excluded](Yoshizawa et al. 2002)
- Studies in kids exposed *in utero* also showed some cardiovascular effects.

**Notes:**
Prenatal mercury exposure associated with increased blood pressure and decreased heart rate variability in 7 year olds (Sorensen et al. ’99)
 Association with decreased heart rate variability still seen in 14 year olds (Grandjean et al. 2004) Heart rate variability is part of organism’s ability to respond to stress.  Decreasing variability is not a good thing.  Has been discussed extensively in the context of particulates. Also saw changes in auditory brainstem evoked potential

Adult effects measured are frank effects at low dose (MI) or endpoints known to be associated with increased risk of cardiovascular disease.
Re Salonen, RfD is 1 ppm hair. 

Heart rate variability is changed in smokers, mercury vapor. Changes are connected with cardiovascular disease.  Don’t know if the change in kids has an adverse effect. Measurements of heart rate variability are considered powerful predictors of cardiovascular disease and death. 
RfD is about 1 ppm in hair.  MI is a severe, frank effect. 

Elemental vapor exposure causes: Acute exp -- tachycardia, increased BP, heart palpitations; “intermediate” – tachycardia and increased BP; chronic – increased risk ischemic heart disease, cerebrovascular disease; positive assoc between heart palpitations and increased urinary Hg.  Some data in rabbits but small study. 

In rats given oral MeHg see persistent increase in systolic BP and decreased heart rate. MeHg may promote progression of arteriosclerosis (carotid thickening). Guallar et al speculate that might be secondary effect of toxic response to autonomic nervous system. 

NRC “ MeHg exposure levels associated with with those effects are comparable to and in some cases lower than those known to cause neurodevelopmental problems.”

## Eating fish – an important part of a healthy diet -- is the main source of exposure to MeHg
Typically about 0.05 to 1.4 ppm (or mg/kg) in fish
Levels vary by species, size, and age of fish
Also, vary by characteristics of waterbody (pH, redox potential, local contamination, and other factors)
Highest in large predatory marine species, such as shark, swordfish, large tuna, some whales, seals
Levels can also be high in predatory freshwater fish, such as pike, perch, tilapia 

- Typically about 0.05 to 1.4 ppm (or mg/kg) in fish
- Levels vary by species, size, and age of fish
- Also, vary by characteristics of waterbody (pH, redox potential, local contamination, and other factors)
- Highest in large predatory marine species, such as shark, swordfish, large tuna, some whales, seals
- Levels can also be high in predatory freshwater fish, such as pike, perch, tilapia

- Exposures to Methylmercury

## Who Is Exposed to MeHg ?

- NHANES (large, continuing CDC study) distribution of MeHg blood levels
- 7.8% women of childbearing age were above RfD
- Blood mercury higher in some ethnic groups
- Fish consumption was associated with increased blood Hg

- Data from smaller, localized surveys show higher blood mercury than NHANES
-  Median blood mercury was 7.1 ppb, people eating fish from AR waters
-  Median was 25 ppb in 6 commercial fishers and family in LA (a)
-  Family in WI, 37- 38 ppb (ate sea bass twice/week)  (b)
-  High income fish-eaters had greater than 80 ppb    (c)

- Fishers, LA

- a

- b

- c

**Notes:**

99 and 00 blacks, Mexican Am , kids 12-19, person 60 and above were oversampled .  Low income whites oversampled in 00. In 99 and 00 all women who said they were pregnant were selected.
Data released in two year groupings
N total = 12,160; n for physical exam = 9282.  Kids = 1250 (705 for phlebotomy); women 16-49 2314 (1709)
African- and Mexican-American kids and
African-American women

## Who Is at Risk for Hg Toxicity?

- Fish is good, nutritious food, consumed in moderation; however, people who consume substantial amounts of contaminated fish and/or marine mammals are “at risk”
- Women of childbearing have potential to expose developing fetus.
- Children eat more food on body weight basis than adults and are still developing, so may be at higher risk than adults
- What about middle aged men?????
- Some occupations
- Artisanal miners, some chloralkali plant workers....
- People living near spills, especially indoor spills
- Possibly some other subgroups using
- traditional medicines, cosmetics, ritual uses...

## Additional Information

## Faroe Islands Study 

- Exposures mainly from pilot whale meat (with Hg levels about 2.0 ppm)
- 900 mother – child pairs
- Measured mercury in hair and cord blood
- Measured neurobehavioral development in children; smaller cohort tested for cardiovascular and other effects
- Exposures associated with deficits in 8 or 10 separate neurobehavioral measures in 7 year old children
- Potential effects of PCB exposure accounted for
- Multiple “benchmark doses” (BMD) range from 24 – 103 ug/ l blood (about 11 ppm hair) which = a dose of about 1 ug/kg/day

**Notes:**
58 is around mid point of range
Adverse Health Effect:  Neuropsychological deficits in ability to learn.
Exposure Producing Effect:
   Fetal blood methylmercury concentration of
 ~ 58 ug/L. Benchmark Dose.
Dose-Response:  Benchmark dose of 58 ug/L associated with a doubling of the prevalence of children scoring in the clinically subnormal range on test of ability to process information and learning.

BNT = Boston Naming test; CPT = Continuous Performance Test; CVLT = California Verbal Learning Test; MCCPP = McCarthy Percieved Performance; MCMT = McCarthy Motor Test  (NZ also had association with Wechsler Intelligence Scale for Children  performance IQ and full scale IQ And Test of Language Development spoken language quotient and grammar. 
Faroes data most within factor of 2; biggest difference bmd vs bmdl is CVLT lowPCB subset ( 7.6x)

## Other Major Studies of MeHg Effects

- New Zealand Study:
- 200 mother – child pairs       (fish and chips)
- Effects noted on several measures in “standard IQ” tests.
- Median BMD = 24 ug/ l blood (9 ppm hair) or about 1 ug/kg/day
- Seychelles.
- 700 mother – child pairs
- Exposures from fish diet (with Hg levels 0.2-0.3 ppm)
- High exposure group had mean mercury hair level = 15 ppm
- No adverse effects identified in children tested at various ages up to 66 months
- NOAEL = 15 ppm hair (1.5 ug/kg/day)     NOAEL = no observed adverse effect level

**Notes:**
NZ = Denver Developmental Screening Test.  McCarthy Scales of Children’s Abilities, Test of Language DevelopmentWecgsler Intelligence Scale for Children.  BMDLs in parens are with outlier removed. Told spoken language BMDL10 = 20 (9.5) ppm hair; WISC performance IQ = 24 (10), WISC full scale = 21 (10), McCarth perception = 17(7.4), McCarth motor 21 (9.8)

Seychelles – some of same tests as in both Faroes and NZ.  
Factors include potential bias in enrolment (but offered participation to all and saw no bias in non-participants)
Hair biomarker is subject to wide variability – may be related to ethnicity
Info on pregnancy, birth and feeding were obtained at 6 months – so may be recall errors
Did not assess nutritional covariates (e.g. Se, PUFA)  -- looking at a new cohort 
May have got different results with different tests (but included a lot of Faroes tests)
Different stat procedures may have given different results (but don’t see any evidence of this)

## Reference Levels, Estimated to Be Safe, Including Fetal Exposure

- FAO/WHO Expert Committee 2003 Provisional Tolerable Weekly Intake (PTWI) = 1.6 ug/kg bw
-      = 0.23 ug/kg/day
- Derived from BMD of 1.5 ug/kg/day divided by 6.4 to account for uncertainty and variability
- U.S. EPA Reference Dose = 0.1 ug/kg/day
- BMD of 1 ug/kg/day divided by 10 to account for uncertainty and variability
- U.S. ATSDR Minimal Risk Level = 0.3 ug/kg/day
- Canada reference level = 0.2ug/kg/day
- European Union level = 0.1 ug/kg/day
- 	FAO/WHO = United Nations Food and Agricultural Organization           (FAO) and World Health Organization (WHO)

## Mercury Exposures for Wildlife

- Wildlife species that rely on fish as a large part of their diet can have elevated mercury levels
- Examples include: otter, mink, raptors, eagles, osprey, seals, some whales
- For example, mercury levels in arctic ringed seals and beluga whales have increased by 2 to 4 times over the past 25 years (based on studies in Canada)

## Effects in wildlife 

- Fish-eating animals and those that prey on fish-eaters are the most exposed population.
- But effects have been measured in insect-eating songbirds
- Mercury affects the nervous system and causes reproductive abnormalities.
- Birds in Minamata had difficulty flying, and exhibited other severe abnormal behavior.  Waltzing cats.
- Mating behaviors may be impaired.
- Laboratory studies have shown impairment in mink, cats, mallards and wading birds
- Field data strongly suggest that adverse effects in common loons are due to accumulation of mercury originating from air emissions.
- Field data also suggest adverse effects due to mercury in the Florida panther, but the origin of this mercury may be from both air and other types of sources.

## Effects in wildlife -- 2

- Adverse effects of MeHg on reproduction can occur at egg concentrations as low as 0.05 to 2.0 mg/kg.
- Eggs of certain Canadian species are in this range
- Concentrations in several other species are  approaching these levels
- Effects on fish are beginning to be demonstrated
- Mercury may also harm soil communities by decreasing microbiological activity

## Choice of Study and EndpointComparison of BMDLs and RfDs

- Choice of Study and EndpointComparison of BMDLs and RfDs

**Notes:**
Adverse Health Effect:  Neuropsychological deficits in ability to learn.
Exposure Producing Effect:
   Fetal blood methylmercury concentration of
 ~ 58 ug/L. Benchmark Dose.
Dose-Response:  Benchmark dose of 58 ug/L associated with a doubling of the prevalence of children scoring in the clinically subnormal range on test of ability to process information and learning.

BNT = Boston Naming test; CPT = Continuous Performance Test; CVLT = California Verbal Learning Test; MCCPP = McCarthy Percieved Performance; MCMT = McCarthy Motor Test  (NZ also had association with Wechsler Intelligence Scale for Children  performance IQ and full scale IQ And Test of Language Development spoken language quotient and grammar. 

Faroes data most within factor of 2; biggest difference bmd vs bmdl is CVLT lowPCB subset ( 7.6x)

## Hg in Fish Species (ppm)

| Species  | Source | Avg Hg  | Max Hg  |
| --- | --- | --- | --- |
| Cod | U.S FDA ’97 | 0.125 | 0.590 |
| Grouper | U.S FDA ’97
U.S. FDA ‘03 | 0.27
0.569 | 0.33
1.205 |
| Mackerel, Atlantic | U.S FDA ’97 | 0.048 | 0.190 |
| King Mackerel, Gulf | U.S FDA ’97 | 0.823 | 2.730 |
| King Mackerel, other | U.S FDA ’97 | 1.128 | 2.900 |
| Red Snapper | U.S FDA ’97
U.S. FDA ‘03 | 0.60
0.154 | 1.46
0.395 |
| Tilapia | Stern et al. ’96 | 0.05 |  |