Recently in Toxicology Category
What has been known is that DEG becomes toxic after it is metabolized to 2-hydroxyethyoxyacetic acid (HEAA) and diglycolic acid (DGA) and that fomepizole, a DEG antidote, inhibits this metabolism. HEAA has generally been fingered as the primary toxicant of DEG poisoning and the cause of associated kidney dysfunction. But a new animal study and in-vitro work suggest that DGA is an important instigator of renal failure (specifically proximal tubular necrosis) in DEG poisoning.
By administering various doses of DEG, with or without fomepizole, to Wister rats, Besenhofer et al determined that the primary DEG metabolite in blood is HEAA after high DEG doses, and that HEAA is probably responsible for the anion gap and low bicarbonate levels seen in DEG poisoning. However, concentrations of HEAA and DGA were similar in renal and hepatic tissues of rats at 48 hours, with a 100-fold "concentrative uptake of DGA" by the kidney. Renal concentrations of both HEAA and DGA correlated with kidney damage, indicating that DGA (as well as HEAA) is a significant contributor to renal injury in DEG poisoning (at least in rats). Importantly fomepizole blocked the formation of both HEAA and DGA, thereby inhibiting renal toxicity.
These animal data are supported by an in-vitro experiment from Landry et al, who incubated human proximal tubule cells with DEG, HEAA, and/or DGA in culture. What the researchers found, to their relative surprise, was that the DEG metabolite HEAA did not produce cell death. However, DGA produced dose-dependent cell necrosis. And on the basis of additional experiments, Landry et al suggested that DGA uptake and its renal accumulation is probably mediated by a cell-based transporter mechanism.
While updating information on the victims of the mass poisoning due to Elixir of Sulfanilamide in 1937 (see here for the work in progress), I came across 3 intriguing articles published just this month on the detection of diethylene glycol (DEG) in consumer products. Two of these articles report the discovery of DEG (albeit at tiny levels) or a chemical cousin, ethylene glycol.
Journal of Toxicology Journal of Medical Toxicology,* investigators from the CDC quantified the amount of DEG and triethylene glycol (TEG), a related compound, in a "convenience sample" of over-the-counter "health products" imported from Asia. The investigators found detectable, but miniscule, DEG levels in 15 (22%) of 68 samples and TEG levels in 2 (3%). The range of DEG levels, in volume-to-volume units, 0.00007%-0.01%, was at least 810 times less than that found in the DEG-contaminated cough syrup in Panama in 2006 (which was reported at a level of 8.1%). The CDC researchers concluded that "these levels probably do not represent an acute public health threat," but that "additional research focusing on why DEG is found [at all] in these products...is needed." Furthermore the minimum amount of DEG necessary for toxicity is unknown.** [See important update/addendum below.]
Then in Molecular Pharmaceutics, investigators at the University of Wisconsin and in South Africa wrote of their discovery of ethylene glycol crystals in a compounded suspension of rifampin. The "exact source" of the ethylene glycol in the antimicrobial is unknown. The authors concluded, "[T]he results of this study show how important it is to ensure that the drug and excipients comply with pharmacopeial or FDA standards."
Perhaps to show that the surveillance for DEG is top-of-mind at the FDA, scientists at the agency wrote in Applied Spectroscopy (who doesn't subscribe?)* that "portable Raman spectrometers" reliably detect DEG in pharmaceutical-grade glycerin at a limit of 0.32%.
* By the way, I do believe that reports of research supported by US tax dollars should be freely and readily available to American citizens, without having to pay for the article (and regardless of the policies of the journal in which an article's published).
** DEG toxicity appears to depend on the production of the toxic metabolite 2-hydroxyethoxyacetic acid (HEAA) through the enzymatic actions of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ADLH), which are known to vary on the basis of genotype and other factors. Variations in enzyme activity may explain the susceptibility of some individuals to DEG poisoning, while others remain unaffected. Notably the administration of fomepizole, an inhibitor of ADH, is a known antidote to DEG poisoning (along with dialysis).
Update: Melgardt de Villiers, lead author of the Molecular Pharmaceutics article, responds by e-mail that the rifampin-derived ethylene glycol crystals were from (or originally observed in) South Africa.
04/06/11 addendum: A review of the full CDC article (which was supplied gratis by the publisher, Springer, at the presumptive request of the corresponding CDC author) reveals the following pertinent facts:
- TEG was assessed in OTC products on the basis of its detection in DEG-contaminated teething syrup in Nigeria (in 2009).
- The convenience sample consisted of OTC liquid- or ointment-based products imported from Asia and sold locally (in Chamblee, Georgia, a suburb of Atlanta). The products were obtained from 9 different stores selling "Asian medicinal products" in the area. (So we're not talking about OTC brandname drugs, like liquid Tylenol.)
- The products were classified by the authors as "dietary/herbal supplements, eye drops/ointment, ear drops/ointment, miscellaneous health-related tonics, nasal spray, throat/cough drops, or topical agent," and had names like "Cough Be Gone," "First Lady Cough and Cold Syrup," and "Shenji Royal Jelly in honey base."
- Most of the 85 products analyzed came from China (71). Ten originated in Hong Kong; 2 came from Singapore, and 1 each were imported from Taiwan and Mayalsia.
- Only 68 products were "analyzable," because 17 weren't water soluble—a requirement for the analytic technique used.
- The median amount of DEG (in volume-to-volume [v/v] units) in the 1995 mass poisoning in Haiti was 14.4%, and that in the 2009 mass poisoning in Nigeria was 19.3% (see the Pathophilia-constructed table below).
- Although information about TEG toxicity is scarce, write the authors, the substance "is considered to have a low order of toxicity." There are only 2 reports of human poisoning with TEG in the medical literature (see here and here). Both were cases of attempted suicide by, for instance, drinking brake fluid.
- The percentage of TEG (v/v) in the Nigeria mass poisoning was 0.6% (vs the miniscule 0.0012% and 0.0018% found in the 2 products in this study).
- On the basis of data from historical poisonings, including the Elixir of Sulfanilamide incident of 1937, the median or average doses of DEG associated with toxicity or lethality in humans range widely from 14 mg of the substance per kg of body mass (Argentina, 1992) to 1500 mg/kg (Haiti, 1995).
- Given the very low levels of DEG detected in the study (and only in some products), the authors speculate that it "may simply be a minor impurity created during the manufacturing processes of chemicals used to formulate drugs and consumer products."
DEG, v/v %
TEG, v/v %
Imported OTC products, 2009
Haiti, 1995 (median)
Panama, 2006 (mean)
Nigeria, 2009 (mean)
Geoff Brumfiel of Nature's The Great Beyond blog provides a series of useful primer posts on radiation numbers (see here and here, for example). The convention is to gauge radiation levels in sieverts—or really, millisieverts (mSv) or microsieverts (microSv).
Most in the health professions are familiar with quantifying radiation exposure (typically from X-rays) in units of gray (Gy), which can be equivalent in a 1:1 fashion with sievert; although the latter unit importantly considers the type of radiation and the type of tissue (eg, brain, abdomen, etc) exposed. The most important caveat, however, when considering radiation exposure from a potential environmental disaster is, not only the radiation level, but the time exposed to that level.
According to TGB blog, radiation levels in Tokyo on the afternoon of March 15 were 0.144 microSv per hour—an elevated, but still tiny, level. By comparison, yesterday's level at the Fukushima nuclear plant gate was 10 mSv per hour (or 10,000 microSv per hour); although there was a transient spike to 400 mSv per hour on Tuesday (March 15).
Brumfiel writes that the cancer risk begins to increase at a threshold of 100 mSv per year. According to various other sources, symptoms of acute radiation sickness (eg, nausea, vomiting) may begin with levels as low as 500 mSv and are almost certain when levels exceed 2000 mSv (or 2 Sv).
According to one Danish study, a chest CT provides a one-time exposure of 6-18 mSv.* A mammogram poses a 3-mSv risk. Other routine background exposures (like those from transcontinental flights or dental radiographs) are provided by Reuters and, of course, Wikipedia.**
* For a rough comparison, the estimated exposure from an abdominal CT is 14 milligray (mGy).
** Unfortunately Wikipedia articles are not consistent in their use of sievert (vs Gy) when describing radiation risks.
03/18/11 update: Today's TGB blog posts an animated map of the recent-past, current, and near-future radioactive fallout from Fukushima, courtesy of Austria's weather service. The wind-directed exposure ranges from 100 mSv per hour (in a transient magenta focus at the plant) to the negligible 100 nanoSv per hour (in a diffuse purple trail, over the Pacific). The model suggests that Tokyo will suffer the greatest exposure (but still at microSv levels), due to changes in wind direction, on March 20.
03/21/11 update: A revision of the animated fallout map from Austria's weather service is at yesterday's TGB blog. The bulk of the fallout, in purple, represents 0.3 microSv per hour—"which corresponds to the amount of the natural background radiation dose." In addition, Forbes's Matthew Herper put the risks of Fukushima's radiation in much-needed perspective.
Because I am a subscriber to Neurology (as an active member of the American Academy of Neurology), this e-mail popped up in my inbox yesterday.
Dear Readers of Neurology,
A story aired last night on World News Tonight with Diane Sawyer disclosing that Dr. Kenneth Shay was on the payroll of, or a consultant to, Proctor and Gamble at the time he peer-reviewed an article authored by Dr. Sharon Nations that was published in 2008 in Neurology, the medical journal of the American Academy of Neurology.
Neurology has a well-established and well-known policy at http://www.neurology.org/site/misc/info_review.xhtml that authors and reviewers must disclose conflicts of interest. Dr. Shay did not disclose any conflict of interest to the Editor-in-Chief of Neurology. Furthermore, it appears that Dr. Shay improperly shared the manuscript authored by Dr. Sharon Nations to Proctor and Gamble, in violation of the journal's confidentiality policy. The American Academy of Neurology considers any violation of these ethics policies to be egregious misconduct, and the Academy's General Counsel is reviewing its options with the editors.
Physician reviewers must disclose all conflicts of interest in order to maintain the integrity of Neurology, which is the world's most widely read and highly cited peer-reviewed neurology journal.
Regarding reports that the publication of Dr. Nations' article was delayed by two years, much of the delay was a result of the time it took the authors to resubmit a revision; the editorial office's review procedure was in line with standard time frames.
We hope you continue to enjoy reading Neurology. We welcome feedback at email@example.com on this and any other issues.
Robert A. Gross, MD, PhD, FAAN
The e-mail refers to this formulaic write-up (ABC News's "Cuomo on the Case"*) of a class-action personal-injury suit, in which plaintiffs are alleging that zinc in Fixodent denture cream (made by P&G) caused their neurologic damage.
The peer-reviewed article in question, published in Neurology in 2008, was featured at this blog (here), at the time of its publication. The study, a small case report, described 4 patients who developed myeloneuropathy (much like what would be expected with severe vitamin B12 deficiency) due to zinc overload (which chelates copper). The subjects, as it turns out, were massive consumers of zinc-containing denture cream (like 2 tubes per day).
Dr. Kennethy Shay, a dentist, was evidently one of the peer reviewers of the Neurology article, who (according to Dr. Gross's e-mail) failed to disclose his financial tie(s) to P&G. In the ABC News piece, the authors of the case report claim that Dr. Shay somehow delayed publication of their study; however, Dr. Gross implies in his e-mail that this was not so.
Corexit, the chemical dispersant being used by BP to break up its massive and growing oil spill, is not the cause of physical symptoms among cleanup workers, says the product's manufacturer, Nalco.
Several news sources, including the NYT, are reporting today that the Naperville, Illinois-based company is defending the safety of Corexit, "when used as directed," although Nalco advises that BP's direct application of Corexit to the spewing oil well is "unprecedented." The Naperville Sun Times says that 993,000 gallons of Corexit have been sprayed or dumped in the Gulf of Mexico as of yesterday. In May, the EPA asked BP to back off on its use of Corexit in the Gulf spill.
So what's in Corexit? It's hard to know exactly, because part of the formula is proprietary. According to the material safety datasheet for Corexit 9500, the "clear, hazy, amber" liquid contains
- 10%-30% hydrotreated light petroleum distillates (a mineral spirit-type solvent, as far as I can tell);
- 1%-5% propylene glycol (a widely used solvent and chemical cousin of ethylene glycol); and
- 10%-30% "organic sulfonic acid salt," which is proprietary (the EPA evidently has the full formula, according to the NYT).
For humans, Corexit appears to be merely a short-term irritant; it is not defined as hazardous or toxic by EPA standards. Safety precautions (eg, gloves, splash goggles) are intended to keep the product away from the skin and eyes. Filter masks are recommended when air concentrations are expected to reach a certain threshold.
Today's PubMed search for "Corexit" returns 59 articles, dating back to 1974. No article pertains to human safety, and 37 articles concern the product's effect on sea life. A search for "Corexit 9500" returns 22 articles, dating back to 1996; 12 pertain to animal or plant effects.
The upshot: Products like Corexit 9500 are very effective oil dispersants, but they may increase (at least temporarily) the concentrations of toxic polycylic aromatic hydrocarbons (PAH) in oil-contaminated water, presumably through their dispersant effects. And there are evidently A TON of variables to consider when deciding to use dispersants—like, the concentration of the crude oil, the "weathered" condition of the oil, water salinity, oil-exposure conditions (eg, whether declining or continuous), and the myriad, myriad, myriad species at risk and their life cycles.
Singer et al (1996). Comparison of acute aquatic effects of the oil dispersant Corexit 9500 with those of other Corexit series dispersants. Corexit 9500 was found to be similarly "toxic" to other Corexit products on early-life stages of the red abalone and kelp forest mysid. The authors, from the University of California, Santa Cruz, wrote that Corexit 9500 is a "reformulation of a long-time industry 'standard,' Corexit 9527, to allow use on higher viscosity oils and emulsions."
George-Ares and Clark (2000). Aquatic toxicity of two Corexit dispersants. Two Exxon employees described the in-vitro "low to moderate toxicity" of Corexit 9500 and Corexit 9527 on "most aquatic species." They also described the variables affecting toxicity (such as species, life stage, duration of exposure, and temperature) and addressed environmental factors that inform the use of dispersants.
Pollino and Holloway (2002). The toxicity of testing of crude oil and related compounds using early life stages of the crimson-spotted rainbowfish (Melantotaenia fluviatilis). Australian academicians determined that Corexit 9500 and Corexit 9527 were less acutely toxic than naphthalene and crude oil-water-dispersant mixtures on the larvae of freshwater rainbowish.
Ramachandran et al (2004). Oil dispersant increases PAH uptake by fish exposed to crude oil. Canadian researchers concluded that the use of dispersants, like Corexit 9500, actually increases the exposure of fish to toxic crude-oil hydrocarbons.
Fuller et al (2004). Comparative toxicity of oil, dispersant, and oil plus dispersant to several marine species. Scientists at Texas A&M observed that crude oil with dispersant was equally or less toxic that crude oil alone on 2 fish and 1 shrimp species. "Unweathered" crude oil (dominated by "soluble hydrocarbon fractions") was more toxic than weathered oil (which was dominated by "colloidal oil fractions"). In declining exposure conditions, weathered and unweathered oil with dispersant were equally toxic to a standardly tested fish species, Menidia beryllina. Both media were dominated by the less toxic "colloidal oil fractions." The consistent finding in this variable-results study: declining-exposure conditions were less toxic than continuous-exposure conditions.
Couillard et al (2005). Effect of dispersant on the composition of the water-accommodated fraction of crude oil and its toxicity to larval marine fish. Researchers from the Canadian Department of Fisheries and Oceans concluded that Corexit 9500, when added to seawater-accommodated fractions of light crude oil, multiplied the concentrations of PAH and was associated with higher mortality rates in larval mummichog.
Liu et al (2006). Field investigation on the toxicity of Alaska North Slope crude oil (ANSC) and dispersed ANSC crude to Gulf killifish, Eastern oyster and white shrimp. Investigators at Louisiana State University found that Corexit 9500 was an effective oil dispersant and facilitated the rapid reduction of hydrocarbon concentrations. At testing conditions, most of the tested juvenile organisms (>83%) survived "well" after 24 hours of exposure. A crude oil concentration higher than 30 ppm was required for "any significant toxic effect."
Ramachandran et al (2006). Influence of salinity and fish species on PAH uptake from dispersed crude oil. Water salinity reduced PAH exposure (by reducing PAH solubility) and the efficiency of dispersants (but only at the highest tested salinity). The Canadian authors concluded that the risk of PAH exposure from dispersed oil will be greatest where salinity is lowest—that is, in coastal waters.
Anderson et al (2009). Preliminary investigation of the effects of dispersed Prudhoe Bay Crude Oil on developing topsmelt embryos, Atherinops affinis. Again, Corexit 9500 increased the hydrocarbon concentrations in water-accommodated oil fractions and this effect appeared to adversely affect the survival of topsmelt embryos, according to researchers of the University of California, Davis.
Jung et al (2009). Biochemical changes in rockfish, Sebastes schlegeli, exposed to dispersed crude oil. Korean investigators confirmed that oil dispersants, like Corexit 9500, increase the exposure of fish to oil hydrocarbons.
Lin et al (2009). Characterization of the metabolic actions of crude versus dispersed oil in salmon smolts via NMR-based metabolomics. Taiwanese scientists concluded that "dispersant treatment significantly decreased the lethal potency of crude oil to salmon smolts," and described several variable metabolic effects that may be useful for monitoring sublethal actions of dispersed oil on fish.
Duarte et al (2010). Acute effects of chemically dispersed crude oil on gill ion regulation, plasma ion levels and haematological parameters in tambaqui (Colossoma macropomum). Investigators in the Amazon reported that chemically dispersed crude oil impairs gill function (ie, ion regulation) in tambaqui to a greater extent than untreated crude oil or Corexit 9500 alone.
Video still of burning Deepwater Horizon rig from YouTube.
06/07/10 addendum: BP's use of 1 million or so gallons of dispersant may also confound the cleanup effort in the Gulf. It's certainly to BP's advantage to obscure the scope of the spill, and Admiral Thad Allen of the Coast Guard says that dispersants "have succeeded at fragmenting one giant spill into 'hundreds of thousands' of mini spills," reports today's Politics Daily. BP's use of dispersant directly on the wellhead is also likely to prevent crude oil from rising to the surface, where it is easier to spot and clean up.
From Pediatrics: a study of tobacco poisonings in young American children.
- From 2006 to 2008, 13,705 cases of tobacco poisoning were reported.
- About 70% of cases occurred in kids younger than 1 year of age.
- Nearly 80% of poisonings were due to the ingestion of cigarettes and (or?) filter tips (vs smokeless tobacco or cigars).
Plus there's commentary on a charming, new Tic Tac-like product from RJ Reynolds: cinnamon- or mint-flavored Camel Orbs, which contain 1 mg of nicotine per pellet. Although the product is new to the market, there has been at least 1 reported case of tobacco poisoning due to the ingestion of Camel Orbs (by a 3-year-old child).
RJ Reynolds also markets flavored Camel Sticks and Camel Strips.
Last year, the FDA was given the authority to regulate flavored cigarettes (but not other flavored tobacco products), thanks to the Family Smoking Prevention and Tobacco Control Act. The agency was quick to ban candy-, fruit-, and clove-flavored smokes in the United States.
Image of Camel Orbs from dissolvables.tobaccopleasure.com.
Occupational exposure to the industrial solvent trichloroethylene increases the risk of Parkinson disease, according to researchers at the Parkinson's Institute and Clinical Center. The California-based, nonprofit organization released its study findings, which have not been presented at a scientific meeting or peer reviewed, on Sunday—apparently by way of press release. The data are scheduled to be presented at the annual meeting of the American Academy of Neurology in April.
According to sources picking up news of the study, data from 198 twin pairs in the World War II Veteran Twins Cohort Registry showed that the risk of PD in individuals with probable exposure to the solvent* was more than 5 times that of twins without probable exposure.** In a MedPage Today piece, an odds ratio (5.5) is reported, but no frequency rates of disease are provided. Also the 95% confidence interval for the odds ratio is very wide (1.02, 30)—indicating that the accuracy of the measured risk is uncertain.
Interest in trichloroethylene exposure as a risk factor in PD extends back to the early 90s, when it was reported by German investigators that a metabolite of the solvent is chemically similar to the neurotoxin MPTP. (The metabolite of MPTP, MPP+, has a predilection for the dopamine-producing neurons of the substantia nigra—the area of the brain that is primarily affected in PD. The MPTP story, itself, is fascinating and the subject of an excellent Nova episode, "The Case of the Frozen Addict," from 1986.)
In 2008, researchers at the University of Kentucky published their study of 30 industrial workers with PD or parkinsonism, who had long-term exposure to trichloroethylene. The study authors suggested that a worker's proximity to the solvent was related to his risk of the movement disorder. These findings were complemented by animal studies, which showed that oral intake of trichloroethylene for 6 weeks resulted in the degeneration of brain areas that are typically affected in PD.
* Presumed on the basis of occupation (eg, aircraft mechanic, electrician).
** The study of twins (and presumably, these are identical twins) largely eliminates any potentially confounding genetic risks of Parkinson disease.
Image of 1886 drawing of PD patient by neurologist Sir William Richard Gowers at Wikimedia Commons.
Unexplained bone-marrow failure (ie, agranulocytosis) in residents of New Mexico, Washington, and Canada led to the discovery of levamisole, an antiparasitic antibiotic, as a prevalent cutting agent in cocaine. A report of the investigation by public health officials, which began last year and identified 21 affected Americans, is available in the latest issue of MMWR.
According to the report, levamisole, as a treatment for rheumatoid arthritis or breast cancer, causes agranulocytosis in 2.5%-13% of patients; however, use of the drug is currently and primarily restricted to veterinary practice (eg, to deworm livestock and aquarium fish).
As of July of this year, about 70% of seized cocaine entering the United States contained levamisole, according to the DEA. The concentration of the additive is approximately 10%, says the agency. Given these statistics, MMWR editors suspect that levamisole-associated agranulocytosis due to cocaine use is vastly underrecognized and underreported.
The reason why levamisole, in particular (versus, say, Italian baby laxative a la Atlantic City) is added to cocaine "remains unclear." Online sources indicate that the antibiotic is a white- to pale cream-colored, odorless or nearly odorless, crystalline powder.
Fifty-four of 57 Nigerian children died between October 2008 and January 2009 after receiving a liquid acetaminophen preparation that was tainted with diethylene glycol (DEG). Exposure to the branded teething product, My Pikin,* was determined in 96% of the identified cases of unexplained acute renal failure (ARF) in the 57 children, according to a retrospective surveillance study performed by Nigerian officials, the CDC, and the US FDA. Their report is available in the latest issue of the MMWR.
The surveillance study was prompted by clusters of unexplained ARF cases in very young children (≤3 years of age) among hospitals in Lagos, Kadun, and Osun in the fall of last year. Initial reports led to the identification of the DEG-tainted product, a full product recall, and the shutting down of the responsible manufacturer in Lagos, Barewa Pharmaceuticals. Despite a nationwide recall and a press release in November of last year, which resulted in the confiscation of 7616 of 15,000 bottles of the contaminated drug, more than a quarter of the affected children received the product after the recall was announced.
Among children for whom data were available, the median time from drug exposure to ARF was 5.6 days (range, 0-24 days), and the mean time between the onset of ARF and death was 6.8 days (range, 1-19 days). Treatments with dialysis, received by 24 children, and the ethylene-glycol antidote fomepizole, received by 2 children, did not appear to prolong survival.
The MMWR editors report at least 12 episodes of DEG contamination in oral or topical medications during the last 70 years, which have caused at least 450 deaths. (Most of these episodes are described here and here.) The contamination was almost always due to the intentional economic-driven substitution of DEG for the more expensive solvents of glycerin or propylene glycol. (An account of the US deaths that occurred in 1937 due to a DEG-tainted antibiotic solution has been provided in numerous serial posts at this blog [search for "sulfanilamide" or "Massengill," for example], and the deceased are listed on this page.)
Prevention of DEG-contaminated drugs is easy and cheap, according to the editors. "Simple, rapid, and low-cost assays" that use thin-layer chromatography are available to detect and measure DEG at levels of 2% in liquid acetaminophen products and 6% in glycerin, they report.
* DEG accounted for 17%-21% of the My Pikin liquid medication by weight in sampled bottles. According to the MMWR, another contaminated acetaminophen-based syrup, made by a different manufacturer, was discovered to contain 0.5% DEG.
Photo of My Pikin Baby Teething Formula from Vanguard.