DMPS is a chelating agent that binds to metals, forming a complex which is renally excreted. It was designed in 1958 in the former Soviet Union as an orally available antidote to “Lewisite,” an arsenic-containing biological warfare agent. DMPS became available to the Western world in 1978 when the German pharmaceutical company, Heyl, began manufacturing and distributing it as a treatment for arsenic, mercury, and lead poisoning [14
]. DMPS is approved in Europe for treatment of heavy metal toxicity, but is not approved by the US FDA for use in the USA.
Chelating agents such as DMPS have received significant attention in recent decades as controversy has arisen regarding a proposed link between mercury and autism [15
]. However, after years of study, no causal relationship between mercury present in vaccines and autism has been established [16
]. Some practitioners continue to assert that mercury and autism are causally linked and treat patients with chelating agents in an effort to both eliminate mercury from the body and treat the autism [2
]. One of the agents used in some autism chelation protocols is a transdermal formulation of DMPS (TD-DMPS).
Pharmacokinetic information is available for the oral and intravenous routes of DMPS administration [18
]. A canine study showed peak plasma concentration occurred 30–45 min after oral administration, and plasma half-life was 43 min (after oral or IV administration) during the terminal elimination phase. After parenteral administration, DMPS was almost exclusively eliminated via the kidneys [20
]. A human study showed that in subjects given 300 mg of oral DMPS, DMPS was detectable in blood samples in its unaltered or reduced form from 30 min to 4 h, and from 30 min to 24 h in its oxidized, disulfide form. The maximum plasma concentration in this study was (mean) 25.3 μM (SE
3.0 μM) [18
]. In the same human study, both oxidized and reduced DMPS were detected in the urine of subjects for a 24-h period, which encompassed six separate collections. Urinary total DMPS levels peaked around 9.5 h[18
]. In contrast, after TD-DMPS, we were unable to detect any reduced or oxidized DMPS in urine.
Scientific studies demonstrating absorption of TD-DMPS through the skin do not exist. The goal of our study was to determine whether topically applied TD-DMPS is absorbed into the body and leads to increased urine mercury excretion. We chose the timing of our assays based on the available data for parenteral and oral DMPS. Though transdermal preparations may be absorbed more slowly than oral ones, the fact that our blood collections at 30, 60, 90, 120, and 240 min, and our 12- and 24-h urine collections all demonstrated no detectable DMPS (except for a single, probably contaminated plasma specimen) provides evidence against any significant skin absorption.
Our assay was validated via several means. This includes the calibration curves created for each individual subject, the blood sample spiked with DMPS after drawing, but before processing, and our control subject who ingested oral DMPS. These mechanisms attest to the robustness of the assay and the strength of our results.
As noted in Table , subject 3 had minutely detectable amounts of DMPS in the plasma at 30 min. This subject did not have detectable plasma levels at any other time, nor was any DMPS detected in his urine. Given the robustness of the rest of the data, the detectable DMPS in plasma was likely due to contamination, as was suspected prior to analysis. The gel was oily and viscous, and the investigator drawing the blood was suspected to have inadvertently contaminated the glove and collection tube while drawing the sample.
A potential weakness of this study is that we used the same weight-based dosing for our adult subjects as is used in children. Children have a larger body surface area (BSA) to weight ratio than adults, and could theoretically have higher blood levels due to greater absorptive surface area. Average BSA for a 2-year-old child is 0.5 m2 (average weight 15 kg), for a 10-year-old child is 1.14 m2, and for an adult is 1.73 m2 (average weight 70 kg). Even if children achieved DMPS plasma levels twice our lower limit of detection, it would still be far below the concentrations reported after oral or IV administration of therapeutic doses of DMPS. We do not think weight-based dosing ultimately affected our study results. There is also potential for variation of drop size depending on the particular dispenser used to measure a dose. It seems unlikely such small variations would affect our results. Although seafood intake was not standardized among subjects, the purpose of encouraging seafood intake in subjects was to increase the likelihood of being able to measure mercury in the urine of subjects and, therefore, detect an effect of DMPS should one exist. Each subject had measureable, but low, urine mercury excretion before and after DMPS, and no subject exhibited an increase in excretion. We do not feel the lack of standardization of seafood intake affected our results.
Many characteristics determine whether a drug is absorbed through the skin. Factors which promote dermal absorption include nonionization at physiologic pH, high lipophilicity, and low molecular weight [21
]. DMPS is ionized at physiologic pH. It is a relatively small molecule (molecular weight 228.27 Da) but is very polar. Drug absorption through the skin is also affected by volatility of the compound, temperature, concentration, skin site, and skin integrity [21
]. Though we followed the instructions provided by the compounding pharmacy for storage and application of the product, the DMPS concentration in the product did decline slightly during the study period. This decline would also occur during the time period a patient would store the bottle during the usage period. It is instructed that the product be applied to intact skin (which is less permeable than compromised skin).
In addition to assaying for DMPS in blood and urine, we measured urine mercury excretion before and after TD-DMPS administration. We collected pre- and post-DMPS urine specimens starting and ending at the same time of day to control for diurnal variation. If TD-DMPS is absorbed and capable of increasing urinary mercury excretion, we would expect to see some rise in the excretion of urine mercury by the subjects, as we do with oral and parenteral administration of DMPS to healthy volunteers [18
]. This did not occur in any of our TD-DMPS subjects. Urine mercury concentration did increase in our control subject, commensurate with rises described in the literature following a “DMPS challenge test” [22
]. There have been reports that subjects with mercury containing dental amalgams show a greater increase in urine mercury excretion after DMPS administration [22
]. Our control subject had no dental amalgams (see Table for dental amalgams in all subjects).