metals – current approaches to interpreting results

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Metals Current Approaches to Interpreting Results. Chris Martin, MD, MSc , FRCPC Associate Professor and Director Institute of Occupational and Environmental Health West Virginia University School of Medicine Morgantown, West Virginia cmartin@hsc.wvu.edu. Interpretation of Labs. - PowerPoint PPT Presentation

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  • Chris Martin, MD, MSc, FRCPCAssociate Professor and DirectorInstitute of Occupational and Environmental HealthWest Virginia University School of MedicineMorgantown, West Virginiacmartin@hsc.wvu.edu

  • Clinically apparent metal toxicity is very uncommon in North AmericaAbnormal measurements in labs are not!Ordered by someone who doesnt know what they are doing and performed by a routine labPerformed by an un$crupulou$ lab Correct interpretation requires attention to test performance

  • BackgroundProperties of testsOn heavy metalsHow to interpret lab results through 7 sequential stepsYou will become a certified MRO Five case discussions

  • Accuracy how close the measurement is to the true valueReliability consistency on repeat measurementsPrecision this relates to the limit of detection of the testValidity 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 testExample consider using the ruler to measureThe width of a femur on an x-rayThe width of a hair

  • Many elements can be measured in hairDoes not mean the person has toxic levels of these elements.

  • Metals originally included only gold, silver, copper, iron, lead, and tin.Dense, malleable, lustrousConduct heat and electricity, cationsMany other elements since added to the list with some of these characteristicsMetalloids 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/cm3Some notion of toxicityUsually includes lead, cadmium and mercuryMany 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 drawnIn 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/LAdditional 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/LReference range: 4-14

  • Beware essential trace elements (zinc, copper, manganese etc.)Labs can (and will) measure themInterpretation problematic for exposure purposesExample: Zinc usually measured in serum

  • Chart2

    10.3

    12.2

    12.1

    11.5

    15.8

    11.5

    12.5

    12

    10

    9.1

    12.4

    9.9

    13.6

    12.3

    10.6

    11

    12.1

    11.8

    9.3

    10.2

    Mean Air Zinc Concentration (mg/m3)

    Serum Zinc Concentration (umol/L)

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

    Sheet1

    Sheet1

    10.3

    12.2

    12.1

    11.5

    15.8

    11.5

    12.5

    12

    10

    9.1

    12.4

    9.9

    13.6

    12.3

    10.6

    11

    12.1

    11.8

    9.3

    10.2

    Mean Air Zinc Concentration (mg/m3)

    Serum Zinc Concentration (umol/L)

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

    Sheet2

    Sheet3

  • Chart1

    1.89

    5.51

    8.28

    4.25

    2.94

    4.18

    1.85

    4.59

    0.87

    5.02

    3.33

    2.71

    2.79

    2.28

    3.74

    3.66

    2.08

    3.32

    7.48

    2.64

    Mean Air Zinc Concentration (mg/m3)

    Urine Zinc (umol/V)

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

    Sheet1

    Sheet1

    1.89

    5.51

    8.28

    4.25

    2.94

    4.18

    1.85

    4.59

    0.87

    5.02

    3.33

    2.71

    2.79

    2.28

    3.74

    3.66

    2.08

    3.32

    7.48

    2.64

    Mean Air Zinc Concentration (mg/m3)

    Urine Zinc (umol/V)

    Figure 5: Plot of Urine Zinc Against Mean Air Zinc (p = 0.04)

    Sheet2

    Sheet3

  • 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 anticoagulantPlasma collect with anticoagulant, spin down promptly to collect supernatantSerum collect without anticoagulant, allow to clot, spin down to collect supernatant

  • Serum and plasma not interchangeableserum levels may be higher than plasma due to invisible hemolysis for elements found at higher concentrations in RBCs (zinc, manganese)

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

  • Pros:Less invasiveProvides longer-term exposure data

  • Cons:External contamination due to adsorbed materialGreat variability in measured valuesLittle to no reference dataWhat 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 amountsCollect in trace-element free tubeKnow your labAll glassware must be washed and properly stored, etc. etc.

  • Cadmium

  • 45-year-old male paint technician whole blood cadmium of 5.9 g/L OSHA biological limit for workers: 5.0 g/L 2000 - 2003, cadmium level 3.1 to 4.3 g/L. He was medically removal from work with cadmium.

  • Blood cadmium 6.1 g/L seven weeks later. Smokes 1.5 to 2 packs of cigarettes daily for 23 yearsNo additional non-occupational exposures to cadmium were identified. No elevation in urine cadmium, urine -2 microglobulin, blood creatinine or urea

  • Not a concern for lead and cadmiumHalf-life for any metal also varies by mediumExample: 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, URINEMercury, conc < 10nmol/LMercury, total H 55 [0-50]nmol/L

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

  • The lowest amount that an analytical method can measure Good labs dont report 0Report should specify detection limitAccuracy of measurement declines as detection limit is approached

  • Mercury (Again)

  • 53-year-old lab technician told she may have been exposed to mercury from microscopeNo signs or symptoms of mercury toxicityRandom urine reported 33.4 nmol/L (high)Reference range 0-15 nmol/LExtensive 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 levelPre-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 medicineDerived from large numbers of measurements on healthy people from general populationDetermine upper and lower limits based on 2 standard deviation from meanConsistent between labsA 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 labs own experienceUsually not occupationally exposedInconsistent

  • Upper limit based on highest measured valueMay also have extremely limited data on massively overexposed cases, these levels may be orders of magnitude higherUnclear what intermediate levels mean

  • Example - Manganese:Nutrition Board of the National Research Councils ESADDI (Estimated Safe and Adequate Daily Dietary Intake) = 2-5 mg day.EPAs 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:LeadCadmiumMercury

  • Lead

  • 32-year-old man two-week history of irritability, diffuse myalgias, and arthralgias.Torch cutting of painted bridge beams with inadequate respiratory protectionWhole blood lead = 6.4 mol/L (132.8 g/dl) Physical exam showed brisk reflexesOther labs normal (including ZPP) except..

  • Increases 3 months after exposurePlateaus 12 months after exposureLacks both sensitivity and specificityOnly two indications:ChronologySurreptitious use of chelation

  • "If you listen long enough, the patient will give you the answer.- Sir William OslerMeasurements of mercury, lead, cadmium usefulBiological measures associated with lead and cadmium generally unhelpfulFor other exposures, either don