Recently in Toxicology Category

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.

Sources are now implicating propofol (Diprivan; sanofi-aventis) in Michael Jackson's death. TMZ reports that police recovered the anesthesia inducer at Jackson's rented home. And ABC News interviewed Jackson's nutritionist, Cherilyn Lee, who stated that the singer asked her for Diprivan, by trade name, 3 months ago. Jackson's alleged intention, bizarre as it may sound, was to be put to sleep at home under the guidance of an anesthesiologist.

In use for more than 2 decades, Diprivan is a rapidly acting (within 40 seconds) IV sedative-hypnotic that is FDA approved for the induction and maintenance of anesthesia and for sedation in an intensive care unit (in both cases, patients are mechanically ventilated). According to the prescribing information, the induction dosage for ICU sedation begins at 5 microg/kg/min and should be titrated (by increments of 5-10 microg/kg/min) to the desired clinical effect. Maintenance rates are generally 5-50 microg/kg/min or higher for adults.*

For anesthesia induction, the typical dosage is 40 mg every 10 seconds in healthy adults younger than 55 years of age; maintenance of anesthesia can be achieved by intermittent boluses of 20-50 mg. However, slow infusion or injection techniques are recommended to avoid apnea and hypotension. Diprivan dosages should be reduced in patients who have received large doses of narcotics.

Common adverse events with Diprivan use include bradycardia or other arrhythmias, hypotension, and apnea. Burning pain or stinging at the injection site, which is also common, may be reduced by preinjecting the vein with a 1% lidocaine solution (1 mL).

Subanesthetic doses of Diprivan may have the potential for abuse by inducing euphoria. Diprivan's abuse potential is particularly high among physicians who have access to the drug—namely, anesthesiologists. An e-mail survey in 2007 indicated that Diprivan abuse has increased substantially in academic anesthesia departments during the last 10 years. Among the 25 reported abusers in the survey, 16 (64%) were resident physicians. Seven (28%) abusers died; 6 of the deceased were resident physicians. In academic centers where abuse occurred, none had established pharmacy protocols to account for the drug (as is done routinely with opiate medications).

In 2008, an anesthesia nurse was convicted of killing a University of Florida student, with whom he was infatuated, by injecting her with propofol in her home. The victim's propofol blood level was 4.3 microg/mL. The expected propofol concentration after a bolus induction dose of 2.5 mg/kg (175 mg for a 70-kg man) is 1.3-6.8 microg/mL.

If a vial or vials of Diprivan were indeed recovered from Jackson's home, it seems almost certain that the medication was palmed by someone who had access, rather than formally prescribed.

Addendum: It also appears that Diprivan can be purchased through online pharmacies. For instance, drugdelivery.ca offers a 50-mL prefilled syringe for $122.99 USD. The completion of a patient questionnaire is necessary (along with payment); it is not clear that a valid prescription is required.

* So for a 70-kg man (~154 lbs), 0.35 mg/min would be administered for induction, and the maintenance dosage ranges from 0.35 to 3.5 mg/min. Vials of Diprivan contain 10 mg/mL and come in 20-, 50-, and 100-mL vials.

Image of Diprivan formulations from APP.

07/04/09 update: Yesterday the AP, citing an anonymous law enforcement official, confirmed that Diprivan was found in Jackson's rented home. CNN also reported that Neil Ratner, an anesthesiologist, traveled with Jackson during his HIStory tour in the mid-90s. Ratner's NY medical license was suspended in 2002 after being convicted of insurance fraud.

The 911 call for Michael Jackson revealed that the singer's hired physician, Conrad Murray, performed CPR (ie, chest compressions) on a bed. Because anybody who's familiar with CPR knows that the procedure should be performed on a hard flat surface (so that chest compressions can be effective), the doctor's resuscitation technique has been called into question.

Now Murray's criminal defense lawyer, Edward Chernoff, offers at least 2 explanations to "Good Morning America" for why the doctor performed chest compressions on a bed. Neither explanation is particularly satisfying. The first is that the bed was "firm," ostensibly serving as a hard, flat surface. The second is that Murray "braced Michael Jackson's back with his hand and compressed his chest with his other hand." This explanation obviously begs the question: If the bed was sufficiently firm, then why was it necessary to brace Jackson's back?

Chernoff goes on to state that Murray checked to determine that his compressions were producing "blood flow." In CPR, typically a second party will determine, by assessing the pulse (eg, the femoral pulse), if chest compressions are mechanically pumping the heart. This assessment can only be done, of course, while chest compressions are being administered. So if Murray was performing CPR with 2 hands, it'd be impossible for him to assess (by himself) the effectiveness of his compressions without an additional hand or two.

Then Chernoff relates that Murray, at some point, moved Jackson off the bed and continued CPR. At what time this action was performed is unknown; it logically took place after the 911 call. But, if Murray believed that his CPR technique was effective on the bed, then why did he later move Jackson onto the floor?

Last, Chernoff states that "it [Murray's CPR] went on for 25, 30 minutes"—suggesting that Murray attempted to revive Jackson on his own for quite some time, before attempting to call 911.

CPR = cardiopulmonary resuscitation. 

N.B.—Chernoff denies that Murray ever administered Demerol to Jackson. He states to GMA, "I can't go into any specifics about drugs that Michael Jackson might have taken the night before, by agreement. I can tell you this: Whatever was taken by Michael Jackson at any time wouldn't have caused his death."

Michael Jackson overdosed on Demerol (meperidine), according to numerous posts on the web, including those at TMZ—the go-to site for bottom-feeders of entertainment news. The web site also reports that Jackson received daily shots of the morphine analog, possibly for years, and that a physician who was at Jackson's home yesterday is "nowhere to be found." The physician possibly administered the dose, which must be given IM or IV.

According to other news sources, Brain Oxman, a Jackson family spokesperson and lawyer, and Liza Minnelli (no stranger to addiction) suggest that Jackson's abuse of prescription opiate medications is longstanding. The speed with which Jackson's speculated cause of death has been transmitted is evident in the fact that the news has already been incorporated into a Wikipedia entry for the drug.

While favored as a treatment for acute pain in the 1980s, Demerol has become considerably less popular among physicians as a short-term analgesic during the last 2 decades, largely because of its toxicity profile and abuse potential.

An autopsy on Jackson's body is to be performed today, with results expected this afternoon, reports MTV.com. Although some toxicology tests are reported to take weeks, measures of opiate medications can be obtained within a day, if not hours.