Recently in Toxicology Category

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.

A lot more obscure than the "seven-fourteen" slang for Quaalude, "420," as a code for Mary Jane, is exhaustively mined by Ryan Grim of the HuffPo. (And God help me, I'm linking to the HuffPo).

HT: KPB, my (what else) college roommate.

Photo of growing marijuana plant from the Department of Justice.

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.

According to the SF Chronicle, by way of Wikipedia, levamisole and cocaine were detected in the body of DJ AM.

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.

A new report may put the kibosh on Halloween face painting.

Minuscule, but measurable, amounts of lead were found in all samples of commercially available brands of face paint that were sent for testing by the nonprofit The Campaign for Safe Cosmetics (TCSC). In addition, 6 of the brands contained levels of heavy-metal allergens (nickel, cobalt, or chromium) that exceeded recommended standards for consumer products (1 ppm).

Ten face paints—many of which were marketed for children—were purchased through Amazon.com and sent for heavy-metal testing at an independent laboratory, Analytical Sciences in Petaluma, California. Four of the brands were manufactured in China. Other countries of origin were the United States (4), the United Kingdom (1), and Spain (1).

Paint Brand	Manufacturer	Location	Heavy Metal Content, ppm
			Pb	Ni		Co		Cr
Alex Face Paint Studio	Alex Toys	China	0.650	—		—		—
Don Post Grease Paint Color Wheel	Don Post Studios	China	0.630	—		—		15
Snazaroo Face Painting Kit	Snazaroo	UK	0.560	5.5		5.5		—
Rubie’s Silver Metallic Fard d‘Argent	Rubie’s Costume Co	USA	0.260	2.1		—		2.2
Ben Nye Lumiere Wheel	Ben Nye Co, Inc	USA	0.190	—		—		—
Wolfe Face Art & FX	Wolfe Face Art & FX	China	0.180	—		—		1.6
Mehron Glow in the Dark Fantasy F-X	Mehron Inc	USA	0.140	—		—		—
Crafty Dab Face Paints Push-Up Crayons	Crafty Dab	China	0.082	—		—		—
Mehron 6-Pack Greasepaint Crayons	Mehron Inc	USA	0.074	4.1		4.8		16
Jovi Make-up	Jovi	Spain	0.054	5.9		—		120
Recommended limit			0		≤1	≤1	≤1

Detectable levels of mercury or arsenic were not found.

The study was prompted by the discovery of lead in top-selling lipsticks in 2007* and reports of heavy metals in kids' face paints sold in other countries (eg, here, here, and here).

TCSC states that there is currently no way to determine if a particular brand of cosmetic contains heavy metals unless testing is conducted by the consumer herself. The organization charges that the FDA "does little to ensure that cosmetics are safe and actually lacks the power to do so...the FDA does not conduct routine testing of cosmetic products and does not have the authority to require companies to conduct pre-market safety assessments of their products or the ingredients in them. The FDA also does not require companies to list heavy metals or other harmful contaminants on product labels, even though they are commonly found in a wide array of personal care products." 

The cost of testing each brand of face paint for heavy metals was $270 per sample.

Whether small amounts of lead in the infrequently used face paint should be a concern is debated; however, there is no good reason for heavy metals to exist in cosmetics or similar products intended for children.

Last winter, contaminated face paint caused skin reactions, some photosensitive, in participants at a Girl Scout event. The paint was manufactured in China.

ppm = parts per million.

* Last month, the FDA reported lead levels in lipstick that were higher than those discovered in 2007 by The Campaign for Safe Cosmetics.

Image of Alex Face Paint Studio, which contained the highest level of lead among the paint brands sampled, from Amazon.com.

A newly released affidavit reveals the last hours of Michael Jackson's life, as told to an LAPD homocide detective by Jackson's personal physician, Conrad Murray. The affidavit, which was used to support a search warrant of Conrad's storage locker in Houston, Texas, also reveals the preliminary and not-so-surprising cause of Jackson's death: a lethal dose of propofol, aka Diprivan. Contrary to popular speculation (and common sense), Jackson did not receive the anesthetic until the mid-morning hours on the day of his death, June 25th (at least that's what the doctor reportedly claimed).

Here's what allegedly went down on that day at Jackson's rented home in Los Angeles:

@ 01:30—Murray gives Jackson a 10-mg tablet of diazepam (Valium) for insomnia. Jackson is unable to sleep.

@ 02:00—Murray gives Jackson lorazepam (Ativan) 2 mg by slow IV push. Jackson is unable to sleep.

@ 03:00—Murray gives Jackson midazolam (Versed) 2 mg by slow IV push. Jackson is unable to sleep.

@ 05:00—Murray gives Jackson another 2-mg dose of lorazepam by slow IV push. Jackson remains awake.

@ 07:30—Murray gives Jackson another 2-mg dose of midazolam by slow IV push. Jackson remains awake.

@ 10:40—After repeated demands by Jackson, Murray administers propofol 25 mg IV after lidocaine pretreatment.

@ 10:50—Murray leaves Jackson's bedside to go to the restroom.

@ 10:52—Murray returns to find that Jackson is not breathing. (Murray stated to investigators that Jackson had been continuously monitored throughout this time with pulse oximetry.) Murray begins CPR (presumably while Jackson remains on the bed) and administers 0.2 mg of flumazenil (Anexate), a benzodiazepine antagonist. Using his cell phone, Murray also calls Jackson's personal assistant and requests that security personnel be sent upstairs for an emergency.

A few minutes later, Murray runs downstairs to the kitchen and (inexplicably) asks the chef to send up Jackson's oldest son. Murray returns to Jackson to continue CPR. Jackson's son responds and summons security detail.

11:18-12:05—Phone records reveal that Murray was on his cell phone for approximately 47 minutes with 3 separate callers; although Murray did not reveal these calls to investigators at the time of the interview.

@ 12:21—Michael Jackson's bodyguard, Alberto Alvarez, goes to Murray and calls 911 on his cell phone.

@ 12:22—An LA Fire Department ambulance responds to Jackson's home. Murray informs the paramedics that he is Jackson's personal physician and that he had continuously administered CPR, for respiratory arrest, until their arrival. Murray also divulges that he had given Jackson lorazepam before his respiratory arrest.

While continuing resuscitation efforts, the paramedics transport Jackson and Murray to the UCLA Medical Center.

@ 14:26—After a protracted effort to revive Jackson at UCLA, Jackson is pronounced dead. Murray allegedly did not reveal to emergency physicians that he had given Jackson propofol. He also refused to sign Jackson's death certificate.

Early in the course of their death investigation, the LAPD evidently could not locate Murray. At Jackson's home, "numerous" bottles of medications were found, which had been prescribed by Murray for Jackson—including the benzodiazepines diazepam, lorazepam, and temazepam (Restoril). Bottles of clonazepam (Klonopin) and the antidepressant trazodone (Desyrel) were also found, which had been prescribed by internist Allan Metzger. And a bottle of the muscle relaxant tizanidine (Zanaflex) had been prescribed to Jackson by his dermatologist, Arnold Klein.

Four days later, investigators, armed with a search warrant, discovered vials of lidocaine, propofol, lorazepam, midazolam, and flumazenil at Jackson's home. None of these medications were associated with an identifiable prescription. The affidavit also reveals that the Drug Enforcement Agency (DEA) could not find a record of Murray purchasing, ordering, or obtaining propofol with his medical license number or DEA number.

Murray admitted that he had been treating Jackson's insomnia with propofol 50 mg IV every night for the last 6 weeks. According to the affidavit, he had successfully reduced the propofol dose to 25 mg on June 22nd, while also administering lorazepam and midazolam to Jackson. The following night, Murray claimed that he was able to induce sleep with only lorazepam and midazolam.

Not sure which is more shocking: The report that at least 20 non-OTC drugs were recovered from Michael Jackson's home or the fact that ABC News is sourcing The Sun on this one. Maybe ABC's reporters were impressed by alleged autopsy information printed last week by the tabloid—namely that Jackson's arms were riddled with needle marks. Yesterday ABC reported the same ("Jackson's arms were scarred with track marks"), citing "investigators."

On the basis of reportage from ABC and The Sun, the partial, cobbled-together list of drugs (save propofol [Diprivan]) found in Jackson's home includes the following (in alphabetical order):

1. Demerol: Generic names, meperidine and pethidine. A fast-acting opioid available in injectable and oral formulations. Legitimate use has become unpopular during the last 2 decades, owing to the drug's potential neurotoxicity and abuse potential. Jackson allegedly took Demerol daily and possibly several times a day.
2. Dilaudid: Generic name, hydromorphone. A morphine derivative available in injectable and oral formulations. Typically used for pain management.
3. Fentanyl: A highly potent synthetic opioid available in injectable, transdermal patch, and "lollipop" formulations. Typically used in anesthesia induction and pain management.
4. Lidocaine: Presumably in the form of low-concentration vials to produce local anesthesia. Possibly used in conjunction with propofol to reduce injection-associated pain.
5. Methadone: A synthetic oral opioid. Most commonly used as a maintenance medication when kicking opioid addiction.
6. OxyContin: Generic name, oxycodone. A wildly popular, semi-synthetic oral opioid. Jackson allegedly took the medication daily.
7. Paxil: Generic name, paroxetine. An orally administered, selective serotonin-reuptake inhibitor (SSRI). Indicated for the treatment of depression, OCD, panic disorder, anxiety disorders, and PTSD.
8. Percocet: Generic ingredients, oxycodone (same as OxyContin) and acetaminophen (eg, Tylenol). Typically prescribed short term for pain relief.
9. Soma: Generic name, carisoprodol (a metabolite of meprobamate, aka Miltown). An orally administered, centrally acting muscle relaxant that potentiates opioid-induced analgesia.
10. Versed: Generic name, midazolam. A very-short-acting benzodiazepine in oral and injectable formulations. Typically used as a premedication before surgical or medical procedures.
11. Vicodin: Generic ingredients, hydrocodone and acetaminophen. Orally administered and should be prescribed short term for pain relief. (N.B.—I've witnessed physicians dispense this drug like Pez candy.)
12. Xanax: Generic name, alprazolam. An orally administered, short-acting benzodiazepine. Prescribed for anxiety and/or sedation.
13. Zoloft: Generic name, sertraline. An orally administered SSRI. Indicated for the treatment of depression, OCD, panic disorder, anxiety disorder, PTSD, and premenstrual dysphoric disorder (which Jackson presumably did not have).

There are a number of permutations for lethal combinations of these drugs, some of which can kill all by themselves. Perhaps more surprising than Jackson's death is his survival—given the duration of his alleged polypharmacy use and dependence.

OCD = obsessive-compulsive disorder; OTC = over the counter; PTSD = posttraumatic stress disorder.

Props must be given to TMZ. Multiple news sources have been citing the entertainment news-gossip web site in the widespread coverage of Michael Jackson's suspect death.

The latest: Edward Chernoff, criminal defense lawyer for Conrad Murray (Michael Jackson's doctor), won't confirm or deny that Murray gave Jackson propofol (trade name, Diprivan). In a phone interview last night, Chernoff reportedly told TMZ, "I have no statement on whether the Dr. prescribed or administered Propofol." Although the lawyer was apparently willing to repeat that Murray did not administer Demerol or OxyContin to Jackson.

In its update, TMZ implies that Chernoff is now backtracking somewhat on last night's statements and "can't speak for anything that was in the [Jackson] home."

Image of Diprivan formulations from APP.