2/20/2020 Toxicology Testing: Being a Detective Eddie Garcia MD Medical Toxicology Fellow University of California San Francisco 1 Disclosures • None 2 Topics • Provoked urine testing • Acetylcholinesterase testing 3 1
2/20/2020 Scenario 45 year old woman is referred to your clinic by her primary care provider after testing positive for mercury. Her PCP arranged for heavy metal testing as part of a work up for a multitude of chronic symptoms including fatigue, intermittent hair loss and myalgias. She collected urine for 24 hours without observing a fast from seafood. Urine: mercury 35 mcg/L, mercury 7 mcg/g creatinine 4 Scenario #2: Provocation 45 year old woman with fatigue, intermittent hair loss and myalgias is referred to your clinic by her primary care provider after testing positive for several heavy metals. Her PCP arranged for her to do testing through an online laboratory service. She collected urine for 6 hours after taking EDTA. 5 6 2
2/20/2020 7 What is provoked testing? Using a chelating agent prior to obtaining urine heavy metal levels. DMSA (succimer) DMPS EDTA 8 Background: Early Provoked Testing 9 3
2/20/2020 Background: Early Provoked Testing 15x 10 Background: Early Provoked Testing • In non-toxic animals models, DFO increases iron excretion in urine. (5x) • In toxic animals models, DFO increases iron excretion in urine. (15x) • The color of urine correlated somewhat with the quantity of excreted iron in the urine • Query: Could urine color reflect the total quantity of iron in the body? 11 Deferoxamine Challenge Test 12 4
2/20/2020 The current state of provoked testing • Deferoxamine challenge for iron poisoning (abandoned) • EDTA challenge for pediatric lead poisoning (abandoned) • Penicillamine challenge for Wilson’s disease (unclear significance) • ACMT 2017 position statement against all provoked metal urine testing. Provoked urine testing for random heavy metals is increasing in popularity 13 Scenario #2: Provocation 45 year old woman with fatigue, intermittent hair loss and myalgias who collected urine for 6 hours after taking EDTA. Elevated: Aluminum, cadmium, lead, nickel, tin and uranium 14 Scenario #2: Provocation • Education: completed high school, college and medical school • Occupation • Cinema worker: Age 16-18 • Research laboratory: Intermittently ages 16-21 • Teacher: Ages 21-23 • Resident (emergency medicine): Ages 28-31 • Physician: Age 32-current • Hobbies: hiking, swimming, reading and being a PTA member • Supplements: none • Spouse: has no exposures at work (data analyst) 15 5
2/20/2020 Problem #1: What is the crime? (AKA what disease are we testing for?) Diseases • Did you unknowingly buy a house with lead paint covering the walls? • Is your coworker slipping cadmium into your water thermos? • Do you think you are eating too much high-mercury content fish? Symptoms • I don’t have as much energy as I used to. • My feet are cold all the time. 16 Pre-Test Probability Pre-Test Probability x Likelihood Ratio = Post-Test Probability Very, very low 17 Problem #2: Comparing fingerprints to toe prints (AKA How do we interpret the data?) 18 6
2/20/2020 How do we interpret the data? 19 Likelihood Ratio Pre-Test Probability x Likelihood Ratio = Post-Test Probability Very, very low Very, very low Very, very, very low 20 Problem #3: The Crime Lab is unregulated (AKA is the data accurate?) • Contamination during collection or processing • Methods of analysis not published • Methods to establish reference ranges not published • Effects of convenience urine collection (6 hours vs 24 hours) 21 7
2/20/2020 22 Many healthy people have abnormal PUMT Group 1: no fish Group 2: 1-2 servings/week Group 3: 3+ servings/week 75% fell into “abnormal” range 23 Chelation as a Placebo • Anecdotally, there are many patients who say chelation makes them feel better. • Grandjean et al 1997 • Randomized, double blinded, study of succimer vs placebo • 50 patients with mercury dental amalgams, all of whom had symptoms they attributed to chronic mercury exposure. • 8 patients in each group reported improvement in symptoms 24 8
2/20/2020 Harms of chelation in a non-toxic person • Depletion of essential metals such as calcium, zinc, magnesium, iron copper and manganese • Chelators such as DPTA can be nephrotoxic • Allergic reactions • Premature diagnostic closure • Chelation at an outpatient clinic can cost $400 or more 25 The Other Side of Chelation • Pro provoked testing • Pro chelation as treatment • We don’t know what “normal” levels are for any metal 26 Take home messages • Provoked urinary heavy metal testing is not recommended. • “Positive” results from provoked testing should not lead to further testing or further chelation. • Chelation can be harmful. • Non-provoked urine metal testing is appropriate if: • There is a known acute exposure to a toxic metal • There is a suspected exposure with correlating symptoms • Part of a biomonitoring program for occupational exposure 27 9
2/20/2020 Epidemiology The organophosphate pesticides are the second most common type of pesticides used in the world (recently overtaken by neonicotinoids) USA: 8,000 exposures in 2015 (20,000 exposures in 1997) 5 deaths per year World: Est. 1-2 million exposures/year (prev 3 million) Est. 100,000-150,000 deaths/year (prev 450,000-600,000) 28 Who is at risk? • Rural populations • Agricultural communities • Agricultural workers • Chemical processing workers • Everyone? 29 Many opportunities for exposure • Found in soil, ground water, surface water, marine organisms • Permissible levels on agriculture products • Typically have a short half-life, though metabolites can retain activity. 30 10
2/20/2020 31 32 AChE Laboratory Testing • RBC cholinesterase • More like cholinesterase found in nerve synapses • More closely mirror recovery • More difficult to measure • Plasma cholinesterase • Less closely mirror cholinesterase found in nerve synapses • Easier to measure and less analytical error • Some OPs inhibit one type of cholinesterase more than the other. Assume the greater change from baseline is correct. 33 11
2/20/2020 OSHA AChE Testing Guidelines • Establish a baseline AChE activity annually. • Baseline should after 30 day of OP-free work • If a person cannot be OP-free for the full 30 days, they can get tested after only one week of being OP-free. • If the difference is less than 10%, that can be used as a baseline. • If more than 10%, then wait another week to be tested for a baseline • Test AChE after 30 hours over 30 days of working with OPs • Remove from OP work if testing shows a decrease in RBC cholinesterase of 30% or plasma cholinesterase of 40% • Return to work at 80% activity. 34 35 Salivary Testing • California study (2000): Crop dusters and harvesters. Salivary cholinesterase activity not related to malathion exposure as measured by urinary malathion metabolites. • North Carolina study (2006): Healthy volunteers. Monitoring salivary cholinesterase activity over 5 weeks without exposure had high variability between measurements. • Singapore study (2009): Lead workers. Monitored over 6 months. Salivary cholinesterase activity was variable over time and had poor correlation with plasma cholinesterase and moderate correlation with RBC cholinesterase • Argentina (2009): Children and mothers exposed to OPs 6 months per year due to agricultural spraying. Salivary cholinesterase activity decreased by 66% in mothers and 86% in children without correlating symptoms. 36 12
2/20/2020 Question 1 Which of the following is an indication for provoked urine metal testing? a) A child with developmental delay who is living in an old home b) A woman who had purposely ingested cadmium salts c) A man with new neuropathy who eats 8-10 servings of fish per week? d) None of the above 37 Question 2 What is not one of the harmful side effects of chelation? a) Stunted growth b) Depletion of essential minerals c) Allergic reactions d) Treatment resistance 38 Question 3 You are part of a biomonitoring program and an agricultural worker is asks how much of a decrease in his baseline cholinesterase activity would necessitate him to stop working with OPs. You answer . . . a) 15% b) 20% c) 25% d) 30% 39 13
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