metals – current approaches to interpreting results

Chris Martin, MD, MSc, FRCPCAssociate Professor and Director

Institute of Occupational and Environmental Health

West Virginia University School of MedicineMorgantown, West Virginia

cmartin@hsc.wvu.edu

Clinically apparent metal toxicity is very uncommon in North America

Abnormal measurements in labs are not!1. Ordered by someone who doesn’t know what

they are doing and performed by a routine lab2. Performed by an un$crupulou$ lab

Correct interpretation requires attention to test performance

Background• Properties of tests• On “heavy metals”

How to interpret lab results through 7 sequential steps• You will become a certified MRO

Five case discussions

Accuracy – how close the measurement is to the true value

Reliability – consistency on repeat measurements

Precision – this relates to the limit of detection of the test

Validity – whether the test measures what it purports to measure

The detection limit is the lowest value that can be measured by a test.

Accuracy declines as measured values approach the detection limit of the test• Example consider

using the ruler to measure

1. The width of a femur on an x-ray

2. The width of a hair

Many elements can be measured in hair

Does not mean the person has toxic levels of these elements.

‘Metals’ originally included only gold, silver, copper, iron, lead, and tin.• Dense, malleable, lustrous• Conduct heat and electricity, cations

Many other elements since added to the list with some of these characteristics

‘Metalloids’ are elements with features intermediate between metals and non-metals. Example: arsenic

A metal having an atomic weight greater than sodium, a density greater than 5 g/cm3

Some notion of toxicity Usually includes lead, cadmium and

mercury Many others may variably be added

to list

Correct use of ‘heavy metal’

Ask seven questions in order. If each issue cannot be satisfactorily

addressed, result is not interpretable and no conclusions can be drawn

In general (with exception of lead, mercury, cadmium), measurements over-utilized, raise more questions than are answered

Manganese

37-year-old man employed in metallizer operation. Vague respiratory symptoms and headache. Has submitted a workers’ compensation claim for “manganese poisoning”.

First Sample: Manganese, plasma 7.2 mcg/L H Normal: < 2.5 mcg/L Limit of Detection = 2.5 mcg/L Additional Notes: “One serum tube pored off from royal blue

(sic)”.

Second Sample: Manganese, plasma 4.4 mcg/L H

Third Sample (after referral to specialist): Manganese (B) 6.0 mcg/L Reference range: 4-14

Beware essential trace elements (zinc, copper, manganese etc.)

Labs can (and will) measure them Interpretation problematic for

exposure purposes Example: Zinc usually measured in

serum

Figure 6: Serum Zinc Against Mean Air Zinc (p = 0.84)

0

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0 5 10 15 20

Mean Air Zinc Concentration (mg/m3)

Seru

m Z

inc

Con

cent

ratio

n (u

mol

/L)

Figure 5: Urine Zinc Against Mean Air Zinc (p = 0.04, r = 0.41)

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0 5 10 15 20

Mean Air Zinc Concentration (mg/m3)

Uri

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inc

(um

ol/V

)

Probably falls in setting of symptomatic overexposure (metal fume fever)

Non-specific inflammatory response(Serum zinc falls in acute MI.)

Urine – 24 hour collection ideal, measure and correct for renal clearance by specific gravity or creatinine clearance

Whole blood – collect with anticoagulant Plasma – collect with anticoagulant, spin

down promptly to collect supernatant Serum – collect without anticoagulant,

allow to clot, spin down to collect supernatant

Serum and plasma not interchangeable• serum levels may be higher than plasma

due to invisible hemolysis for elements found at higher concentrations in RBC’s (zinc, manganese)

Many metals (As, Pb, Cr, Cd) incorporated into keratin through binding with sulfhydryl groups

Pros:• Less invasive• Provides longer-term exposure data

Cons:• External contamination due to adsorbed

material• Great variability in measured values• Little to no reference data• What is the denominator?

Hair growth rate varies with gender, age, body location, season.

Not all metals equal!Example: • Exposure and toxicity from tetra-alkyl lead

better reflected in urine measurements • Exposure and toxicity from inorganic lead

better reflected in whole blood measurements

Recall: levels are often present in “trace” amounts

Collect in trace-element free tube Know your lab

• All glassware must be washed and properly stored, etc. etc.

Cadmium

45-year-old male paint technician whole blood cadmium of 5.9 µg/L

OSHA biological limit for workers: ≤5.0 µg/L

2000 - 2003, cadmium level 3.1 to 4.3 µg/L.

He was medically removal from work with cadmium.

Blood cadmium 6.1 µg/L seven weeks later.

Smokes 1.5 to 2 packs of cigarettes daily for 23 years

No additional non-occupational exposures to cadmium were identified.

No elevation in urine cadmium, urine β-2 microglobulin, blood creatinine or urea

Not a concern for lead and cadmium Half-life for any metal also varies by

medium• Example: mercury

Mercury

49-year-old nurse with persistently elevated urine mercury levels.

Concerned she has chronic mercury poisoning from numerous dental amalgams, no other exposures identified.

Polymyalgia rheumatica and hypertension. Recommended urgent replacement of all

mercury amalgam fillings (cost = $5000) followed by IV chelation therapy.

MERCURY, URINE Mercury, conc < 10 nmol/L Mercury, total H 55 [0-50]

nmol/L

MERCURY, URINE Mercury, conc 10 nmol/L Mercury, total H 54 [0-50] nmol/L

The lowest amount that an analytical method can measure

Good labs don’t report “0” Report should specify detection limit Accuracy of measurement declines as

detection limit is approached

Mercury (Again)

53-year-old lab technician told she may have been exposed to mercury from microscope

No signs or symptoms of mercury toxicity Random urine reported 33.4 nmol/L (high)

• Reference range 0-15 nmol/L Extensive IH survey of lab reveals air and

spot check samples below detection limit during operation of microscope

Lab cites:

Brodkin E, Copes R, Mattman A, Kennedy J, Kling R and Yassi A. Lead and mercury exposures: Interpretation and action. CMAJ 176(1):59-63.

These authors in turn, cite data from NHANES.

They clearly indicate that cutoff was 95%ile and that investigation for possible exposure should not occur until values are 5x that level

Pre-shift limit < 250 nmol/L (FIOH) Lab: We rely on MD to interpret

results in context.

Normal ranges are what we usually deal with in medicine

Derived from large numbers of measurements on healthy people from general population

Determine upper and lower limits based on 2 standard deviation from mean

Consistent between labs A value outside of range is “abnormal”

(although will occur in 5% of healthy people)

Apply to most metal measurements (except lead, cadmium, mercury)

Limited data from small, convenience sample either from published study or lab’s own experience• Usually not occupationally exposed

Inconsistent

Upper limit based on highest measured value

May also have extremely limited data on massively overexposed cases, these levels may be orders of magnitude higher

Unclear what intermediate levels mean

Example - Manganese:• Nutrition Board of the National Research

Council’s ESADDI (Estimated Safe and Adequate Daily Dietary Intake) = 2-5 mg day.

• EPA’s LOAEL (lowest-observable-adverse-effect level) for water is 4.2 mg day for a 70-kg individual.

(Source: Greger JL. J Nutr 1998 Feb; 128 2Suppl:368S-371S)

NHANES provides data on ‘normal’ ranges for:• Lead• Cadmium• Mercury

Lead

32-year-old man two-week history of irritability, diffuse myalgias, and arthralgias.

Torch cutting of painted bridge beams with inadequate respiratory protection

Whole blood lead = 6.4 μmol/L (132.8 μg/dl)

Physical exam showed brisk reflexes Other labs normal (including ZPP)

except…..

Increases 3 months after exposure Plateaus 12 months after exposure Lacks both sensitivity and specificity Only two indications:

1. Chronology2. Surreptitious use of chelation

"If you listen long enough, the patient will give you the answer.” - Sir William Osler

Measurements of mercury, lead, cadmium useful

Biological measures associated with lead and cadmium generally unhelpful

For other exposures, either don’t measure them or be sure you know what you are doing

In practice, you will most frequently be trying to calm people down who have already had ‘abnormal’ test results

The MRO’s Handbook