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House Oversight and Government Reform Committee Investigation into Johnson and Johnson’s Recall of Children’s Tylenol and Other Children’s Medicines

Statement of
Joshua M. Sharfstein, M.D.
Principal Deputy Commissioner
U.S. Food and Drug Administration
Department of Health and Human Services

Before the
Committee on Oversight and Government Reform
U.S. House of Repersentatives

May 27, 2010
Introduction
Mr. Chairman and Members of the Committee, I am Joshua M. Sharfstein, M.D., Principal Deputy Commissioner, U.S. Food and Drug Administration (FDA or the Agency), which is an Agency of the Department of Health and Human Services. Thank you for the opportunity to discuss the Agency’s regulation of drug manufacturing, our oversight of McNeil Consumer Healthcare, LLC (McNeil), and lessons learned from the ongoing investigation into quality concerns at McNeil.

FDA Oversight of Drug Manufacturing
Under the Federal Food, Drug, and Cosmetic Act, FDA is charged with, among other things, ensuring that drugs marketed in the United States are safe and effective, and are manufactured in accordance with current Good Manufacturing Practice (cGMP).

The cGMP regulations for drugs contain minimum requirements for the methods, facilities, and controls used in manufacturing, processing, and packing of a drug product. The regulations are intended to ensure purity, potency, and quality of drug products, and to prevent unsafe products from reaching consumers.

Under the cGMP regulations, each manufacturer sets specifications for its own products for such factors as potency, stability and purity, and puts in place a quality system that ensures those specifications are met. Critical to the cGMP process is that a company must meet its own standards.

A violation of cGMP does not necessarily mean that a product is hazardous to the public. It does indicate, however, a breakdown in a manufacturer’s quality system and is an indication that a company needs to take effective steps to fix the problem promptly.

FDA inspects facilities to ensure compliance with cGMP standards. These inspections occur on average for domestic facilities every two to three years. We increase the frequency of inspections for facilities when warranted by past problems or by products that are difficult to manufacture or are especially high risk.

When on site, FDA inspectors identify gaps in manufacturing standards and discuss with companies how they can fix them. Firms may choose to recall products when there are cGMP violations, especially when those violations have a significant impact on product quality or safety.

For drugs, patterns of non-compliance or non-compliance that put the public’s health at risk leads to appropriate enforcement action by the Agency, including warning letters, seizures, injunctions and criminal prosecution.

Oversight of McNeil Consumer Healthcare, LLC (McNeil)
McNeil makes a variety of over-the-counter (OTC) products for the U.S. market from four manufacturing facilities in the United States and Canada. Over the last several years, FDA has had growing concerns about the quality of the company’s manufacturing process. These concerns have led to a number of unsatisfactory inspections and consumer recalls. FDA has inspected the company’s facilities with an increased frequency, and in February 2010, the Agency took the extraordinary step of convening a meeting with the management of the parent company, Johnson & Johnson, to express concern about a pattern of non-compliance.

Prior to 2009. Before 2009, FDA investigators identified several problems with cGMP compliance at facilities run by McNeil. These problems included laboratory controls, equipment cleaning processes, and a failure to investigate identified problems. The company generally fixed the specific problems, and the Agency inspected the firm regularly.

Spring/Summer 2009. At its Fort Washington facility, McNeil makes a wide variety of OTC products, including a large number of OTC liquid products for children.

In May and June 2009, FDA identified several cGMP violations, including McNeil’s failure to meet its own standard for quality in one of the ingredients in OTC liquids.

McNeil’s standard for this ingredient, known as microcrystalline cellulose, required that there be no gram negative bacteria. McNeil purchased the cellulose in partial lots that had not tested positive for this objectionable bacteria. The vendor tested other partial lots from the same large master lot and found a certain gram negative bacteria called B. cepacia. According to cGMP standards, McNeil should not have used any partial lots from this master lot.

In reviewing the situation, FDA scientists concluded that the risk to the public was remote. All of the drums used tested negative for the bacteria B. cepacia, all of the final product tested negative, and FDA agreed with the company’s assessment that this bacteria would be very unlikely to grow in the final product.

Yet, because the company had not kept to its standard, it represented a cGMP violation, and the company initiated a recall of almost eight million bottles of finished product in August 2009.

Fall 2009. At its Las Piedras, Puerto Rico, facility, McNeil makes a large number of OTC pills for the U.S. market.

In the fall of last year, FDA became aware that McNeil had received reports of products from this facility having a musty odor. Yet, McNeil had not fully investigated these reports for about a year and did not notify FDA despite the requirement that such reports be referred to the Agency within three days.

FDA inspectors urged McNeil to conduct a complete investigation, which eventually identified the source of the odor to be a chemical, called 2,4,6-Tribromoanisole or TBA, which was in the air because of a pesticide used on the wood of the pallets used to store empty medication bottles. McNeil initiated a series of recalls as the scope of the problem became clear.

The risk posed to the public by this problem included potential temporary, non-serious gastrointestinal reactions – including nausea, stomach pain, vomiting, or diarrhea. Very little is known about the chemical TBA, but in the small quantities transferred to the products, it is not thought to pose a serious risk for long-term health problems.

On January 15, 2010, FDA issued a warning letter to McNeil expressing serious concerns about the company’s control over the quality of its drugs and the company’s failure to aggressively investigate and correct quality problems. This letter identified significant violations of the cGMP regulations. FDA noted that neither upper management at Johnson & Johnson nor at McNeil assured timely investigation and resolution of the issues.

January and February 2010. In early 2010, FDA conducted focused inspections of McNeil at both the Las Piedras and Fort Washington facilities to follow up on a reported problem. The report identified a 6-year-old child who died. Prior to his death, the child had been given several products manufactured by McNeil at these facilities. FDA tested the products the child had taken for potential contamination, and all results were negative. Based on the results of the testing and the results of the inspection, FDA did not find evidence to link the products to the child’s death.

February 2010. On February 19, 2010, senior compliance staff from FDA’s Center for Drug Evaluation and Research and from FDA’s field organization met with senior officials from McNeil and its parent company, Johnson & Johnson. Attendees included the President of McNeil, the Company Group Chairman for OTC at Johnson & Johnson, as well as a number of Quality Assurance executives from both companies.

This was an extraordinary meeting. FDA requested that senior officials from Johnson & Johnson attend the meeting so they would be on notice regarding FDA’s rising concerns about whether McNeil’s corporate culture supported a robust quality system to ensure the purity, potency and safety of its products. FDA also raised concerns about Johnson & Johnson’s oversight of McNeil due to recent multiple recalls of McNeil products and recent warning letters FDA had issued to both McNeil and its parent company, Johnson & Johnson. Based on the Fort Washington and Las Piedras inspections in 2009 as well as the firm’s recent compliance history, FDA expressed its significant concern that there was a pattern of conduct including failure to report material information to FDA in a timely manner, miscalculating and/or misstating risks and benefits of their products, and reactive vs. proactive approaches to product quality problems. FDA told the company’s leadership that significant, immediate steps were needed to address issues of compliance and quality, especially in investigating product quality issues so that the company could take preventive action to avoid problems.

The Agency learned that McNeil was taking several major steps to address these issues, including implementing management reporting structure changes, hiring new managers, and engaging a third party manufacturing consultant. FDA indicated that it would continue to monitor closely and consider further action, and that it was concerned about whether the company’s corporate culture was appropriately focused on product quality issues.

April 2010. In April, FDA inspectors returned to McNeil’s Fort Washington facility. This inspection was scheduled sooner than usual due to McNeil’s recent history of compliance problems, including numerous recalls and cGMP deficiencies discovered in the June 2009 Fort Washington inspection, which had a significant impact on the scheduling of the April 2010 inspection.

Days before the inspectors arrived, McNeil shut down manufacturing because of manufacturing issues, including particulates found in a number of liquid medications. These particulates included acetaminophen, cellulose, nickel, and chromium. FDA inspectors identified a range of cGMP violations. These included the company failing to meet its own specifications for bacteria and particulates and, for one Tylenol product, the possibility of higher than expected concentrations of Tylenol per dropper.

In reviewing the situation, FDA scientists concluded that the risk posed to the public by these problems was remote. FDA did not find evidence that McNeil used raw materials that its tests found to be positive for bacterial contamination and all lots of finished product were tested by McNeil and found negative for bacterial contamination. The particulates would be expected to pass through the gastrointestinal tract. While there was a potential for higher concentrations of Tylenol per dropper, none of the final products released for sale tested with high levels. In addition, the increase in potency would not be expected to cause adverse effects.

Although the public health risk from these quality problems is low, these problems should never have occurred, and the cGMP failures at the facility that caused them were unacceptable. Following cGMP requirements assures that products are consistent in their safety and effectiveness and failure to follow those procedures undermines consumer confidence. On April 30, 2010, McNeil announced a voluntary recall of over 136 million bottles of liquid infants’ and children’s products.

Next Steps in FDA Oversight of McNeil

Based on the pattern of concerns found at McNeil’s facilities, FDA is working with the company to address its systemic quality issues. The Agency is closely monitoring the implementation of a corrective action plan developed by McNeil that includes significant enhancements to its quality system, organizational changes, and senior management oversight.

FDA will continue to investigate issues related to the Fort Washington facility including oversight related to renewal of manufacturing operations at that facility, to evaluate the facility’s suppliers, and evaluate the compliance of all other McNeil facilities. FDA will also take steps to help ensure that when the facility begins manufacturing again it will be able to produce safe products. FDA is also considering additional enforcement actions against the company for its pattern of non-compliance which may include seizure, injunction or criminal penalties.

Adverse Event Evaluation
It is understandable that many Americans, hearing about these large recalls, would wonder whether or not their children were put at risk. In assessing this question, FDA considers two basic sources of information – first, our assessment of the manufacturing problems themselves, and second, adverse event reports to the Agency.

As I discussed earlier, FDA analyzed the various manufacturing problems. Based on the circumstances in each case, our experts believe the risk for any child in the United States was remote.

FDA has also looked at adverse events reported to the Agency. FDA receives these reports and often requests and reviews medical records, coroner’s reports, and other supplementary data sources.

When we have adequate information about a case, the Agency reviews these reports to determine what role, if any, the medication played in the development of an adverse event. We can find that the medication likely had no role in the adverse event, that the medication’s activity as a drug could have caused a serious side effect, or that a quality problem may have contributed to the outcome.

All drugs have side effects, and some of the McNeil reports may reflect the side effects of OTC medications. Other reports appear unrelated to the medications.

So far, FDA has no cases with evidence that a product quality issue contributed to a significant adverse health outcome. We are continuing to receive information about certain cases and we will update the public and the Committee should our assessment change.

Lessons Learned
Every investigation presents an opportunity for FDA to improve our effectiveness in protecting the public health. One lesson to be drawn from the McNeil story is that it is important for the Agency to even more fully consider the corporate structure when investigating and enforcing the law. FDA will be developing new procedures to use what we learn at one facility in guiding our inspections of other facilities run by the same company.

FDA is also using these events as part of an ongoing review of our recall process. FDA has already made significant changes to its approach to recalls when there are urgent, life-threatening product quality concerns. For example, in recent months, FDA has moved aggressively to support several urgent food recalls. FDA is now looking at our process for clear expectations and standards with respect to other types of recalls, such as those undertaken by McNeil.

We will continue to work with Congress to secure additional authorities that could assist us in assuring product quality and acting more quickly when product quality issues occur.
FDA will also be considering enforcement actions in this case as part of the Agency’s ongoing changes in enforcement. FDA Commissioner Dr. Margaret Hamburg has called for FDA’s enforcement to be “vigilant, strategic, quick, and visible.” A range of activities are underway at the Agency to bring this vision to reality, including strengthening our criminal enforcement of FDA’s laws.

As we continue these efforts, as well as our other regulatory work, we will focus on entire companies and their systems in addition to focusing on specific violations, individuals, and sites, much as we are doing in the McNeil situation.

Conclusion
Thank you for the opportunity to explain FDA’s oversight of drug manufacturing and our engagement with McNeil. I look forward to your questions.

“Gentle on little tummies.. When it comes to reducing fever or relieving pain in infants, INFANTS’ TYLENOL® has been the brand recommended most by pediatricians for the last 20 years. INFANTS’ TYLENOL® works differently than other pain and fever medicines. It also won’t upset little stomachs…. anhydrous citric acid, butylparaben, D&C red no. 33, FD&C Blue no.1, flavors, glycerin, high fructose corn syrup, microcrystalline cellulose and carboxymethylcellulose sodium, propylene glycol, purified water, sodium benzoate, sorbitol solution, SUCRALOSE, xanthan gum.”

The Search For Sweet by Burkhard Bilger for The New Yorker – May 22, 2006

“The substance in the flask seemed to have all the makings of an excellent insecticide. It was a fine crystaline powder and its molecules were full of chlorine atoms, like DDT. ..by taking an eye-dropper full of sulfuryl chloride – a highly toxic chemical – and adding it to a sugar solution, one drop at a time. In the violent reaction that followed, a wholly new compound was born: 1′, 4,6,6′-tetrachloro-1′,4,6,6′-tetra-deoxygalactosucrose. “It isn’t of any use as an insecticide,” Hough told me recently, “That was tested.” But it has proven useful as a food. In its pure form, it is known as sucralose. When mixed with fillers and sold in bright yellow sachets, it’s known as Splenda, the best-selling artificial sweetener in America.”

Sucralose was declared safe by the Food and Drug Administration in 1998, but most of the taste researchers I talked to won’t eat it. “I look at that structure and I have an irrational fear of it,” one of them said.”

http://archives.newyorker.com/?i=2006-05-22#folio=040

J Toxicol Environ Health A. 2008;71(21):1415-29. doi: 10.1080/15287390802328630.
Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats.
Abou-Donia MB1, El-Masry EM, Abdel-Rahman AA, McLendon RE, Schiffman SS.
Author information

Abstract
Splenda is comprised of the high-potency artificial sweetener sucralose (1.1%) and the fillers maltodextrin and glucose. Splenda was administered by oral gavage at 100, 300, 500, or 1000 mg/kg to male Sprague-Dawley rats for 12-wk, during which fecal samples were collected weekly for bacterial analysis and measurement of fecal pH. After 12-wk, half of the animals from each treatment group were sacrificed to determine the intestinal expression of the membrane efflux transporter P-glycoprotein (P-gp) and the cytochrome P-450 (CYP) metabolism system by Western blot. The remaining animals were allowed to recover for an additional 12-wk, and further assessments of fecal microflora, fecal pH, and expression of P-gp and CYP were determined. At the end of the 12-wk treatment period, the numbers of total anaerobes, bifidobacteria, lactobacilli, Bacteroides, clostridia, and total aerobic bacteria were significantly decreased; however, there was no significant treatment effect on enterobacteria. Splenda also increased fecal pH and enhanced the expression of P-gp by 2.43-fold, CYP3A4 by 2.51-fold, and CYP2D1 by 3.49-fold. Following the 12-wk recovery period, only the total anaerobes and bifidobacteria remained significantly depressed, whereas pH values, P-gp, and CYP3A4 and CYP2D1 remained elevated. These changes occurred at Splenda dosages that contained sucralose at 1.1-11 mg/kg (the US FDA Acceptable Daily Intake for sucralose is 5 mg/kg). Evidence indicates that a 12-wk administration of Splenda exerted numerous adverse effects, including (1) reduction in beneficial fecal microflora, (2) increased fecal pH, and (3) enhanced expression levels of P-gp, CYP3A4, and CYP2D1, which are known to limit the bioavailability of orally administered drugs.

Splenda: The Artificial Sweetener that Explodes Internally
By: Shane Ellison, MS for The People’s Chemist

“Splenda contains the drug sucralose. This chemical is 600 times sweeter than sugar. To make sucralose, chlorine is used. Chlorine has a split personality. It can be harmless or it can be life threatening.
In combo with sodium, chlorine forms a harmless “ionic bond” to yield table salt. Sucralose makers often highlight this worthless fact to defend its’ safety. Apparently, they missed the second day of Chemistry 101 – the day they teach “covalent” bonds.
When used with carbon, the chlorine atom in sucralose forms a “covalent” bond. The end result is the historically deadly “organochlorine” or simply: a Really-Nasty Form of Chlorine (RNFOC).
Unlike ionic bonds, covalently bound chlorine atoms are a big no-no for the human body. They yield insecticides, pesticides, and herbicides – not something you want in the lunch box of your precious child. It’s therefore no surprise that the originators of sucralose, chemists Hough and Phadnis, were attempting to design new insecticides when they discovered it! It wasn’t until the young Phadnis accidentally tasted his new “insecticide” that he learned it was sweet. And because sugars are more profitable than insecticides, the whole insecticide idea got canned and a new sweetener called Splenda got packaged.
To hide its dirty origin, Splenda pushers assert that sucralose is “made from sugar so it tastes like sugar.” Sucralose is as close to sugar as Windex is to ocean water.”

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I have stumbled upon one factor that has been overlooked in Autism research and infant and children’s health. Pediatricians often recommend giving infants and children Tylenol and Mortin (for infants over 6 months) for pain management prior or just after they’ve received a vaccine. What public and health care professionals do not know is that there is an excipient in the infant and children Tylenol and some of the Motrin formulations that contains a chlorocarbon (or organochloride) utilized as the sweetening agent.


To access Children’s Tylenol ingredient list click here.

Sucralose or what is commonly known as Splenda is the organochloride or chlorocarbon utilized in the suspension fluids. The invention of sucralose or Splenda was documented in the New Yorker article, “The Search For Sweet,” by Burkhard Bilger – May 22, 2006.

The substance in the flask seemed to have all the makings of an excellent insecticide. It was a fine crystaline powder and its molecules were full of chlorine atoms, like DDT. ..by taking an eye-dropper full of sulfuryl chloride – a highly toxic chemical – and adding it to a sugar solution, one drop at a time. In the violent reaction that followed, a wholly new compound was born: 1′, 4,6,6′-tetrachloro-1′,4,6,6′-tetra-deoxygalactosucrose. “It isn’t of any use as an insecticide,” Hough told me recently, “That was tested.” But it has proven useful as a food. In its pure form, it is known as sucralose. When mixed with fillers and sold in bright yellow sachets, it’s known as Splenda, the best-selling artificial sweetener in America.”

Sucralose was declared safe by the Food and Drug Administration in 1998, but most of the taste researchers I talked to won’t eat it. “I look at that structure and I have an irrational fear of it,” one of them said.

To access this article view on the link below. The New Yorker does charge a small fee to access this archived issue.


The Search For Sweet by Burkhard Bilger for The New Yorker – May 22, 2006


THE LETHAL SCIENCE OF SPLENDA, A POISONOUS CHLOROCARBON by James Bowen, M.D.

James Bowen explains the impacts of Splenda (sucralose).

“Splenda/sucralose is simply chlorinated sugar; a chlorocarbon. Common chlorocarbons include carbon tetrachloride, trichlorethelene and methylene chloride, all deadly. Chlorine is nature’s Doberman attack dog, a highly excitable, ferocious atomic element employed as a biocide in bleach, disinfectants, insecticide, WWI poison gas and hydrochloric acid.

“Sucralose is a molecule of sugar chemically manipulated to surrender three hydroxyl groups (hydrogen + oxygen) and replace them with three chlorine atoms. Natural sugar is a hydrocarbon built around 12 carbon atoms. When turned into Splenda it becomes a chlorocarbon, in the family of Chlorodane, Lindane and DDT.

“It is logical to ask why table salt, which also contains chlorine, is safe while Splenda/sucralose is toxic? Because salt isn’t a chlorocarbon. When molecular chemistry binds sodium to chlorine to make salt carbon isn’t included. Sucralose and salt are as different as oil and water.

“Unlike sodium chloride, chlorocarbons are never nutritionally compatible with our metabolic processes and are wholly incompatible with normal human metabolic functioning. When chlorine is chemically reacted into carbon-structured organic compounds to make chlorocarbons, the carbon and chlorine atoms bind to each other by mutually sharing electrons in their outer shells. This arrangement adversely affects human metabolism because our mitochondrial and cellular enzyme systems are designed to completely utilize organic molecules containing carbon, hydrogen, oxygen, nitrogen, and other compatible nutritional elements.

“By this process chlorocarbons such as sucralose deliver chlorine directly into our cells through normal metabolization. This makes them effective insecticides and preservatives. Preservatives must kill anything alive to prevent bacterial decomposition.”

Dr. Bowen believes ingested chlorocarbon damage continues with the formation of other toxins: “Any chlorocarbons not directly excreted from the body intact can cause immense damage to the processes of human metabolism and, eventually, our internal organs. The liver is a detoxification organ which deals with ingested poisons. Chlorocarbons damage the hepatocytes, the liver’s metabolic cells, and destroy them.

In test animals Splenda produced swollen livers, as do all chlorocarbon poisons, and also calcified the kidneys of test animals in toxicity studies. The brain and nervous system are highly subject to metabolic toxicities and solvency damages by these chemicals. Their high solvency attacks the human nervous system and many other body systems including genetics and the immune function. Thus, chlorocarbon poisoning can cause cancer, birth defects, and immune system destruction. These are well known effects of Dioxin and PCBs which are known deadly chlorocarbons.”

Dr. Bowen continues: “Just like aspartame, which achieved marketplace approval by the Food and Drug Administration when animal studies clearly demonstrated its toxicity, sucralose also failed in clinical trials with animals. Aspartame created brain tumors in rats. Sucralose has been found to shrink thymus glands (the biological seat of immunity) and produce liver inflammation in rats and mice.

“In the coming months we can expect to see a river of media hype expounding the virtues of Splenda/sucralose. We should not be fooled again into accepting the safety of a toxic chemical on the blessing of the FDA and saturation advertising. In terms of potential long-term human toxicity we should regard sucralose with its chemical cousin DDT, the insecticide now outlawed because of its horrendous long term toxicities at even minute trace levels in human, avian, and mammalian tissues.

Researchers have known for a long time that chlorinated compounds impact liver functionality. Rachel Carson discussed chlorinated compounds in Silent Spring. She also discusses Methoxychlor, another organochlorine once used as an insecticide, and it’s toxicity when combined with other chlorinated compounds like DDT.

One of the most significant facts about the chlorinated hydrocarbon insecticides is their effect on the liver. Of all the organs in the body the liver is most extraordinary. In its versatility and in the indispensable nature of its functions it has no equal. It presides over so many vital activities that even the slightest damage is fraught with serious consequences. Not only does it provide bile for the digestion of fats, but because of its location and the special circulatory pathways that converge upon it the liver receives blood directly from the digestive tract and is deeply involved in the metabolism of all the principal foodstuffs. It stores sugar in the form of glycogen and releases it as glucose in carefully measured quantities to keep the blood sugar at a normal level. It builds body proteins, including some essential elements of blood plasma concerned with blood-clotting. It maintains cholesterol at its proper level in the blood plasma, and inactivates the male and female hormones when they reach excessive levels. It is a storehouse of many vitamins, some of which in turn contribute to its own proper functioning.

Without a normally functioning liver the body would be disarmed–defenseless against the great variety of poisons that continually invade it. Some of these are normal by-products of metabolism, which the liver swiftly and efficiently makes harmless by withdrawing their nitrogen. But poisons that have no normal place in the body may also be detoxified. The “harmless” insecticides malathion and methoxychlor are less poisonous than their relatives only because a liver enzyme deals with them, altering their molecules in such a way that their capacity for harm is lessened. In similar ways the liver deals with the majority of the toxic materials to which we are exposed.

Our line of defense against invading poisons or poisons from within is now weakened and crumbling. A liver damaged by pesticides in not only incapable of protecting us from poisons, the whole range of its activities may be interfered with. Not only are the consequences far-reaching, but because of their variety and the fact that they may not immediately appear they may not be attributed to their true cause…..

The effect of a chemical of supposedly innocuous nature can be drastically changed by the action of another; one of the best examples is a close relative of DDT called methoxychlor (Actually, methoxychlor may not be as free from dangerous qualities as it is generally said to be, for recent work on experimental animals shows a direct action on the uterus and a blocking effect on some of the powerful pituitary hormones–reminding us again that these are chemicals with enormous biological effect. Other work shows that methoxychlor has a potential ability to damage the kidneys.) Because it is not stored to any great extent when given alone, we are told that methoxychlor is a safe chemical. But this is not necessarily true. If the liver has been damaged by another agent, methoxychlor is stored in the body at 100 times its normal rate, and will then imitate the effects of DDT with long-lasting effects on the nervous system. Yet the liver damage that brings this about might be so slight as to pass unnoticed. It might have been the result of any number of commonplace situations–using another insecticide, using a cleaning fluid containing carbon tetrachloride, or taking one of the so-called tranquilizing drugs, a number (but not all) of which are chlorinated hydrocarbons and possess power to damage the liver.

This raises very serious questions. Infant and children’s pharmaceutical excipients, inactives, or inerts (Take your pick on the term) need serious review. The Johnson & Johnson McNeil Fort Washington Facility is now closed. The FDA inspection review showed chronic failures in quality and consistency of the oral suspension formulations. This is the same facility where they make sucralose and utilized it in their infant and children’s Tylenol and Motrin formulations. Johnson & Johnson’s McNeil failed to understand the potential implications of utilizing a chlorocarbon (or organochloride) as a sweetener in infant and children’s pharmaceuticals. Parents give their infants and children Tylenol and Motrin products to help relieve their pain and suffering not knowing that something in that product may have serious long term health consequences. Has Splenda or sucralose ever been tested for its synergistic properties? Could sucralose impair liver functionality and cause other poisons or toxins to be absorbed at an accelerated rate? Those are the questions that need immediate answers.

The FDA inspection report is deeply disturbing in light of this information.

Observation 3
Control procedures fail to include adequacy of mixing to assure uniformity and homogeneity.

Control procedures used did not validate the manufacturing processes that caused variability in the characteristics of the drug product. For examples, the agitation speeds and time to reach [Blacked out] in the hold tank during processing of the [blacked out] super potent batches that failed APAP (end of run) assays, [blacked out] released batches, and the demonstration batch. The firm did not demonstrate the adequacy of mixing to assure uniformity and homogeneity for Infant’s Dye-Free Tylenol Suspension Drops, Formula [blacked out] using a [blacked out] batch in a [blacked out] hold tank. Agitation and tank levels with [blacked out] the amount of liquid) in a [blacked out] hold tank were evaluated with one demonstration bulk batch, lot ]blacked out] packaged as lot [blacked out] The [blacked out] batches into [blacked out] hold tanks used [blacked out] and the agitator was shut off at [blacked out] using the weight of [blacked out] for the [blacked out] batch in a [blacked out] hold tank. With the [blacked out] super potent batches, APAP concentrated at the end run when the agitator was shut off at [blacked out] in the tank).

To review the complete inspection report click on the link below to review the PDF.


Food & Drug Administration Facility Inspection Results for McNeil Consumer Healthcare, Division of McNeil-PPC, Inc.

The inspection results are also available here at this site.
https://renchemista.wordpress.com/2010/07/13/fda-facility-inspection-results-for-mcneil-ppc-fort-washington-pa-4192010-4302010-childrens-tylenol-motrin-recalls/

J Toxicol Environ Health A. 2008;71(21):1415-29. doi: 10.1080/15287390802328630.
Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats.
Abou-Donia MB1, El-Masry EM, Abdel-Rahman AA, McLendon RE, Schiffman SS.
Author information

Abstract
Splenda is comprised of the high-potency artificial sweetener sucralose (1.1%) and the fillers maltodextrin and glucose. Splenda was administered by oral gavage at 100, 300, 500, or 1000 mg/kg to male Sprague-Dawley rats for 12-wk, during which fecal samples were collected weekly for bacterial analysis and measurement of fecal pH. After 12-wk, half of the animals from each treatment group were sacrificed to determine the intestinal expression of the membrane efflux transporter P-glycoprotein (P-gp) and the cytochrome P-450 (CYP) metabolism system by Western blot. The remaining animals were allowed to recover for an additional 12-wk, and further assessments of fecal microflora, fecal pH, and expression of P-gp and CYP were determined. At the end of the 12-wk treatment period, the numbers of total anaerobes, bifidobacteria, lactobacilli, Bacteroides, clostridia, and total aerobic bacteria were significantly decreased; however, there was no significant treatment effect on enterobacteria. Splenda also increased fecal pH and enhanced the expression of P-gp by 2.43-fold, CYP3A4 by 2.51-fold, and CYP2D1 by 3.49-fold. Following the 12-wk recovery period, only the total anaerobes and bifidobacteria remained significantly depressed, whereas pH values, P-gp, and CYP3A4 and CYP2D1 remained elevated. These changes occurred at Splenda dosages that contained sucralose at 1.1-11 mg/kg (the US FDA Acceptable Daily Intake for sucralose is 5 mg/kg). Evidence indicates that a 12-wk administration of Splenda exerted numerous adverse effects, including (1) reduction in beneficial fecal microflora, (2) increased fecal pH, and (3) enhanced expression levels of P-gp, CYP3A4, and CYP2D1, which are known to limit the bioavailability of orally administered drugs.

http://www.ncbi.nlm.nih.gov/pubmed/18800291

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The Search For Sweet by Burkhard Bilger for The New Yorker – May 22, 2006

The substance in the flask seemed to have all the makings of an excellent insecticide. It was a fine crystaline powder and its molecules were full of chlorine atoms, like DDT. ..by taking an eye-dropper full of sulfuryl chloride – a highly toxic chemical – and adding it to a sugar solution, one drop at a time. In the violent reaction that followed, a wholly new compound was born: 1′, 4,6,6′-tetrachloro-1′,4,6,6′-tetra-deoxygalactosucrose. “It isn’t of any use as an insecticide,” Hough told me recently, “That was tested.” But it has proven useful as a food. In its pure form, it is known as sucralose. When mixed with fillers and sold in bright yellow sachets, it’s known as Splenda, the best-selling artificial sweetener in America.”

Sucralose was declared safe by the Food and Drug Administration in 1998, but most of the taste researchers I talked to won’t eat it. “I look at that structure and I have an irrational fear of it,” one of them said.

To read the full article click below.


The Search For Sweet by Burkhard Bilger for The New Yorker – May 22, 2006

It’s extremely informative but you will have to pay to view it. Well worth the $3.

I also found a copy of this article here.

http://www.princeton.edu/~amoroz/2006/05/search-for-sweet.html

The substance in the flask seemed to have all the makings of an excellent insecticide. It was a fine crystalline powder, easy to imagine spraying over a field, and its molecules were full of chlorine atoms, like DDT. To make it, Shashikant Phadnis, a young Indian chemist at Queen Elizabeth College, in London, and his adviser, Leslie Hough, had begun by taking an eyedropper full of sulfuryl chloride–a highly toxic chemical–and adding it to a sugar solution, one drop at a time. In the violent reaction that followed, a wholly new compound was born: 1′, 4, 6, 6-tetrachloro-1′, 4, 6, 6′-tetradeoxygalactosucrose.

On that late-summer day in 1975, Phadnis was told to test the powder, but he misunderstood: he thought that he needed to taste it. And so, using a small spatula, he put a little of it on the tip of his tongue. It was sweet–achingly sweet. “When I reported my findings to Les, he asked if I was crazy,” Phadnis remembers. “How could I taste compounds without knowing anything about their toxicity?” Before long, though, Hough was so delighted with the substance that he dubbed it Serendipitose and tried putting some in his coffee. “Oh, forget it,” he said, when Phadnis reminded him that it might be toxic. “We’ll survive!”

Over the next year, Hough and Phadnis worked with the British sugar company Tate & Lyle to make more than a hundred chlorinated sugars, finally settling on one that had three chlorine atoms and was about six hundred times as sweet as sugar. “It isn’t of any use as an insecticide,” Hough told me recently. “That was tested.” But it has proved useful as a food. In its pure form, it is known as sucralose. When mixed with fillers and sold in bright-yellow sachets, it’s known as Splenda, the best-selling artificial sweetener in America.

People will eat almost anything, it seems, as long as it’s sweet. And, until fairly recently, this mental programming served them just fine. When Columbus introduced cane to the New World, the anthropologist Sidney Mintz has noted, sugar was an exotic luxury. Most Europeans had never eaten sugar, but they quickly developed a taste for it. By 1700, the Americas had become a vast sugar mill and the English were eating four pounds per person per year. By 1800, they were eating eighteen pounds; by 1900, ninety pounds. But nowhere was the rise of sugar as dramatic as in the New World. Last year, the average American consumed about a hundred and forty pounds of cane sugar, corn syrup, and other natural sugars–fifty per cent more than the Germans or the French and nine times as much as the Chinese.

Artificial sweeteners are both a symptom of this craving and an attempt to curb it. Some two hundred million Americans now use them, but rarely with much enthusiasm. Like Splenda, the most popular products were all discovered by accident; none of them taste much like sugar; and there is no final verdict on their safety. Saccharin was found over dinner in 1879, by a chemist who was working with coal-tar derivatives and forgot to wash his hands properly. It’s used in Sweet’N Low in the United States, where it was listed as a possible carcinogen until 2000, and is still banned as a food additive in Canada. Aspartame, which is used in Equal and most diet sodas, was found in 1965, by a chemist who was testing new drugs for gastric ulcers and licked his fingers before picking up a piece of paper. A recent study by the National Cancer Institute found no evidence that aspartame caused cancer in people, but an Italian study found that it caused cancer in rats. Sucralose was declared safe by the Food and Drug Administration in 1998, but most taste researchers I talked to won’t eat it. “I look at that structure and I have an irrational fear of it,” one of them said. “I’ve seen the safety studies, and you feed it to rats and mice forever and nothing happens. But it just scares me.”

Inventing a sweetener with even a little of sugar’s appeal is one of the hardest tasks in food science. It’s less like imitating the taste of Coke or vanilla than like trying to imitate water–another simple but astonishingly versatile compound. Sugar’s sweetness only begins to explain our devotion to it. You can freeze it, cook it, candy it, and caramelize it. It adds bulk to baked goods and helps them to brown. Sugar is a powerful preservative. It triggers the taste buds almost instantly, fades quickly without aftertaste, and has a voluptuous mouthfeel. Even its potency can’t easily be improved. Artificial sweeteners may be thousands of times as sweet by volume, but their flavor loses intensity with repeated tasting. Sugar stays sweet.

Of course, sugar can also make you fat, put diabetics into a coma, and make your children run screaming in circles. In the past twenty years, it has helped to double the number of obese Americans and rotted untold millions of teeth. Sugar may be the single most unhealthy part of the American diet, yet until recently there was little hope of finding a tastier, more wholesome substitute. Thousands of chemicals were known to be sweet, but none of them tasted or behaved like sugar. If all artificial sweeteners had been discovered by accident, the reason was simple: No one knew how to make them from scratch.

In the early nineteen-eighties, the NutraSweet Corporation launched what would become a twenty-year effort to find a better sweetener. The company’s first product, aspartame, had been introduced in 1981 and had quickly become America’s best-selling sugar substitute. Because it was composed of two common amino acids, aspartame was advertised, at first, as an almost natural product–“If you’ve had bananas and milk, you’ve eaten what’s in NutraSweet.” But aspartame also had problems. It couldn’t be used in baking, because it broke down under high heat, and it tended to lose its sweetness over time. NutraSweet had higher hopes for its successor. “Sugar is in trouble,” the company’s president, Robert Shapiro, said. “You can’t do anything to improve the product.”

The search for Sweetener 2000, as it was later known, turned into a race of sorts between two groups on opposite sides of the Atlantic. In Mount Prospect, Illinois, outside Chicago, Shapiro and assembled a team of more than a hundred chemists, taste researchers, and support staff. The NutraSweet scientists knew that the tongue’s taste buds are made up of clumps of fifty to a hundred cells, layered like an onion and tipped by chemical receptors. But they weren’t sure how many kinds of receptors there were, how they functioned, or how they sent their signals to the brain. So the team worked by trial and error. They began by building computer models of existing sweetener molecules, modified them a few atoms at a time, and then fed the most promising candidates to mice. If the mice didn’t “drop dead,” as one member of the team put it recently, the compounds were sent to an outside lab for a series of sweetness tests, culminating in a fifteen-member taste panel.

In France, meanwhile, Claude Nofre and Jean-Marie Tinti, two chemists at Claude Bernard University, in Lyons, were searching for sweeteners in a more old-fashioned way. Nofre had come to NutraSweet’s attention when he invented a potent substance called superaspartame. Although it didn’t seem to be toxic, super-aspartame had some unsettling similarities to cyanide, so NutraSweet gave Nofre a grant to try again. The funding wasn’t enough to pay for computer modelling or elaborate taste tests, so Nofre and Tinti relied on Tinkertoy-type molecular models, on Nofre’s instincts for the inner workings of taste buds, and on the evidence of their own tongues. “We tasted all of the compounds, all of them!” Nofre told me. “NutraSweet thought we were crazy.” After seven years, the Mount Prospect team had identified around five hundred new sweeteners; Nofre and Tinti eventually found more than two thousand.

The winning compound, now called neotame, is a version of aspartame to which Nofre and Tinti attached a chain of carbon and hydrogen atoms. Neotame doesn’t lose its flavor or break down when you cook with it, and it’s about eight thousand times sweeter than sugar. In 2002, after more than a hundred human and animal studies, neotame was approved by the F.D.A. This year, it made its first appearance in American stores–in Ice Breakers candies, SunnyD Reduced Sugar orange drink, Mr. Fizz sodas from Wal-Mart–and will now be judged by the only standard that really matters: how it tastes.

NutraSweet’s test kitchen in Chicago, here its new products are developed, is on the ninth floor of a labyrinthine office building downtown. Known as the Sweet Spot, it’s staffed by a team of “beverage formulators” in white lab coats and looks like the set of an industrial video from the nineteen-fifties–fluorescent lights, vinyl floor, and Formica counters bristling with scales, homogenizers, refractometers, pH meters, and other electronic gizmos. When I went there in January, for a taste test of neotame, I was met by Craig Petray, the company’s chief executive, and Ihab Bishay, the director of research. Petray, who is forty-five, has a linebacker’s build, a clean-shaven head, and an almost soldierly faith in his sweeteners. While he cited statistics and sales strategies, Bishay–a plump, genial Egyptian with a black goatee and rectangular glasses–quietly laid out the scientific evidence.

He began by setting nine plastic cups in front of me, each one filled with water flavored with a different artificial sweetener. The cups were a miniature overview of the global sweetener market. If their sizes had corresponded to actual consumption, the one with saccharin in it would have been by far the largest, with about sixty per cent of the total volume. The one with aspartame would have been next, with about twenty per cent, and the rest would have been tiny. Sucralose, the sweetener in Splenda, accounts for less than five per cent of worldwide consumption, although it has conquered the tabletop market in the United States. Neotame claims less than one per cent, most of that in China. Sugar wasn’t in the lineup, but its cup would have dwarfed the rest: last year alone, almost three hundred billion pounds of sugar was consumed worldwide–about three times more than all other sweeteners combined. Clearly, neotame had a lot of convincing to do.

The tasting that followed felt a bit like “To Tell the Truth”–the old game show where celebrity panelists had to identify the bona-fide contestant from among a group of impostors. One by one, the sugar substitutes gave themselves away with the equivalent of a thick foreign accent or a laughably inauthentic manner. Saccharin had sugar’s quick punch and lack of aftertaste but was accompanied by a mildly bitter or metallic edge. So were cyclamate and acesulfame-K, two sweeteners often used in place of saccharin. As partame and sucralose didn’t have any off flavors, but their sweetness came on too slowly and stuck around too long. Tagatose, a low-calorie carbohydrate made from lactose, tasted nearly identical to sugar–its chemical structure is quite similar–but even in moderate quantities it acted as a laxative. “Don’t drink too much,” Petray said. “The plane trip will not be comfortable,” Bishay added.

Worst of all were the sweeteners found in health-food stores. Stevia, made from a South American shrub of the same name, seemed to combine all the failings of its artificial cousins: slow onset, heavy aftertaste, bitterness, and other disagreeable flavors. (Monsanto, NutraSweet’s former owner, considered genetically modifying stevia in order to make it less bitter, but the project was self-defeating: stevia’s only real selling point is its natural quality.) Thaumatin, derived from the West African katemfe fruit, was said to be two thousand times as sweet as sugar, but it tasted like nothing at first. Then, slowly, like the opening chords of a Wagner overture, the flavor began to build: deep and faintly dissonant, with echoes of licorice and cough syrup. Chewing-gum makers often add thaumatin to round off flavors and make them last longer, but taken alone, at a high concentration, it was truly awful.

“This is the whole world of sweeteners,” Bishay said. “These are the primary candidates, and there’s no really good one. They are not the answer.” That left neotame. Its taste was strong, clean, and straightforward–like aspartame, with a deeper bottom–but it took a while to register on the tongue and fingered forever. Its molecules seemed to lock onto the taste receptors so stubbornly that later arrivals had nowhere to bind; by the fourth or fifth sip, the water was nearly tasteless. If I’d been chewing stevia leaves or katemfe fruit all my life, neotame might have seemed like a great improvement. But I hadn’t. When I sipped some sugar water afterward, the taste came as a blessing: bright, vivid, quick-blossoming, with unexpected hints of fruit and flowers. It wasn’t hard to see why Europeans in the Middle Ages considered sugar not a staple but a spice.

“Pretty good sweetener, this sugar,” Petray said, with a resigned smile. NutraSweet had given up on finding a true replacement for it, he added: there would be no successor to neotame. Instead, the company was focussing on blending sweeteners in order to minimize their weaknesses, then mixing them with sugar to get the same taste with fewer calories. This was where neotame came into its own. It cost a tenth as much as sugar and half as much as sucralose. It had no off-putting flavors, and it heightened the tastes of other foods much as sugar did. “We think the sweetener world in the future is going to be a blend world,” Petray said.

He set three more cups in front of me, filled with orange soda. One or two were made with natural sugars; one or two were sweetened with a mixture of sugars, neotame, and acesulfame-K. My job was to pick the soda that tasted different from the two others. “Triangle tests” like this were harder than straight comparisons, Petray said, and this blend was one of NutraSweet’s best. Acesulfame-K’s quick bite offset neotame’s slow, lingering sweetness. Still, I had no trouble telling the sodas apart. Petray and Bishay tried again, with different blends, replacing as little as twenty per cent of the sugars. They even brought out two cakes that Bishay’s wife had made–one with sugar, one with a neotame blend. The cakes managed to fool me, but in every other case I easily spotted the outlier. “In a taste panel, this would pass every time,” Petray told me at one point, a bit exasperated. “As an average consumer, there is no way you would say it was different.” But to my taste, that day, there was still no replacement for sugar.

Humans are connoisseurs of sweetness. No other species is so particular. Cats can’t taste sugar; neither can many dogs. Most other animals can’t taste artificial sweeteners. (We know this, in part, thanks to an enterprising Swiss anthropologist named Dieter Glaser, who has offered them to fish, hedgehogs, tree shrews, primates, elephants, horses, cows, sheep, pigs, dogs, cats, mice, birds, reptiles, kangaroos, and swamp wallabies.) But after a million years of devoted omnivorousness–of climbing trees, swatting at bees, and scouring the landscape for any hint of sugar–people can taste every sweetener, and they can tell them apart.

Charles Zuker, a molecular biologist at the University of California at San Diego, thinks that a craving so subtle and so deep can’t be satisfied by trial and error. You can’t just take chemical potshots at the tongue, he says. You have to isolate its taste receptors, understand how they work, and find ways to trigger them. Like Petray, Zuker doesn’t think that sugar can be replaced. But the right chemical might do something even better, he says. It might make foods with less sugar taste just as sweet.

Zuker, whose name means “sugar’ in Yiddish, give or take a consonant or two, jokes that he was destined to do this work. He Was born in Chile, the grandson of Polish and Russian refugees from the Holocaust. He played with microscopes when most boys were playing soccer, and went to Jesuit school, although his family was Jewish. By the age of fifteen, he was in college, by nineteen he was attending graduate school at M.I.T., and by twenty-three he had earned his doctorate. Now forty-eight, he has dedicated his life to the senses, scientifically and otherwise. He owns a house on the cliffs above Del Mar, drives a Porsche Twin Turbo to work, and is married to his college sweetheart, a Spanish instructor at the university who resembles the actress Charo.

The first time I saw Zuker, he was giving the keynote address at a conference on the senses, in Washington, D.C. He was slouched at the podium in a suede jacket and weathered jeans, ricing an audience of neuroscientists in suits. A pair of reading glasses was perched on his slender, balding head, and the Rolling Stones’ tongue-and-lips logo was projected on a screen behind him. Until quite recently, he told the audience, the prevailing view of how taste receptors work was “idiotic.” Most scientists believed that each cell in a taste bud carried receptors for all five basic flavors—sweet, sour, salty, bitter, and umami, the savory taste of protein. When food or drink passed over them, each cell sent an elaborately coded message to the brain, like a shortwave broadcast in five languages. “It made no sense,” Zuker told me later. “Sweet and bitter prompt fundamentally different behaviors. Sweet is to determine caloric content; bitter is to warn you against toxins. It’s the difference between life and death.” Why would the same cell send both signals?

Zuker’s laboratory in San Diego is stocked both with bottles of hazardous chemicals and with bags of exotic treats. On the day I visited, one of the tables was piled with Warheads: hard candies so sour that the package bore a picture of a puckered face with a mushroom cloud exploding from it. When I asked Zuker about them, he leaned back in his chair and curled one arm around his head. “The students bring in new sensory experiences every week,” he said. “We had spicy ginger gummies last time.” He told me to help myself to a bag of shrivelled Chinese wolfberries, on the counter. The berries had a sweet, strangely meaty flavor. After I’d had a few dozen, I asked him if there was any danger in eating too many. “We’ll find out,” Zuker said, grinning.

As a rule, today’s students refuse to offer their tongues in the service of science, so Zuker keeps a large colony of mutant mice in a building across the street. Some of them can taste bitter but not sweet, others sweet but not bitter, and so on–more than a thousand mice in all. In the past few years, Zuker and the geneticist Nicholas Ryba, at the National Institutes of Health, together with a succession of graduate and postdoctoral students, have used these animals to help identify the taste receptors. They began, in 1998, by scanning RNA sequences from the tongue and homing in on the most likely genes. They then bred mice that lacked the genes, to see how their tastes were affected. Within two years, Zuker’s team had located the entire family of twenty-six bitter receptors. By 2001, they’d found the receptors for sweet and umami as well. Zuker’s team wasn’t alone in making some of these discoveries–biologists at Harvard, the Monell Chemical Senses Center, in Philadelphia, and other labs also found receptors–but his mice provided the decisive evidence. It was an astonishing feat of genetic sleuthing. “I was stupefied,” Claude Nofre told me. “I thought they would be found in the year 3000.” To celebrate, the journal Cell put a chocolate cake on its cover, flanked by two mice.

The taste cells that Zuker found were much simpler than biologists had imagined. Instead of bristling with every kind of receptor, each cell was tuned to a single frequency: some cells detected sweet, others bitter, still others umami. (The receptors for salty and sour have yet to be found.) There seemed to be no elaborate signals to encode and decode, no danger that the brain might misread that little part about arsenic in a lengthy molecular report about mangoes and bananas. The tongue, like any good electrical system, was wired with well-insulated, well-labelled lines. All the brain had to do was follow instructions.

To demonstrate, Zuker led me to a small, tiled room with two cages full of mice. One set had white fur, red eyes, and untampered genes; the others were brown-haired, black-eyed mutants. The mice had not had water for a while, so they were extremely thirsty. We were going to offer them three bottles filled with different liquids, Zuker said, and he invited me to take a taste. The first was just water, the second was sugar water, and the third–“Don’t slurp it!” Zuker said–was the most unpleasant thing I’d ever had. The water had been dosed with the world’s bitterest known substance, denatonium benzoate, a “freak molecule” that’s often put into pesticides and household cleaners to prevent accidental poisonings. After a minute or so, it showed no signs of releasing its fierce grip on my tongue. I popped a Warhead in my mouth to try to blast it off. This was a mistake. The denatonium combined with the acids in the candy to trigger something like a mushroom cloud inside my head. “Let that teach you a lesson about the biology of taste,” Zuker said.

The white mice didn’t like the denatonium, either. When Zuker gave them the two other liquids, they lapped them up so quickly that their tongues were a blur, but they could stand only a lick or two of denatonium before running to the other side of the cage. The mutants, though, had had their bitter receptors knocked out genetically, so the denatonium was tasteless to them. Zuker’s team had also engineered mutants that reacted to bitter as if it were sweet. They’d even taken a mouse’s sweet taste cells and inserted a receptor for a tasteless, artificial compound that the mouse then guzzled as if it were sugar water. “The animal kingdom sees the world as a binary choice,” Zuker concluded. “Something is sweet not because it tastes sweet but because it activates cells in your brain that say, ‘This is good.'” Bitter foods activate ceils that signal, “This is bad.” “It is an absolutely gorgeous example of Darwinian evolution,” Zuker said. “Otherwise, you eat it and you die.”

Zuker’s theory strikes some researchers as simplistic; isolated taste cells seem to respond to a number of tastes, not just those from a single receptor. But few doubt the practical value of the receptors he has found. Pharmaceutical firms have long used certain receptors to search for new compounds and to create targeted drugs with fewer side effects. The same technology can now be used to search for new sweeteners. Zuker has little interest in doing this work. “I am a pure basic scientist,” he told me. “I’m trying to figure out how the brain works, not how to make chemicals taste better.” But he isn’t averse to letting others do it for him. In 1998, Zuker and a small group of other scientists and businessmen founded Senomyx, a biotech firm devoted to taste. Senomyx now has a patent on the use of the sweet receptor, patents pending on the umami and bitter receptors, and partnerships with Kraft, Coca-Cola, Nestlé, Campbell’s, and Cadbury-Schweppes. In the next few years, Senomyx and its partners hope to reinvent the flavors in our food without anyone really noticing.

The Senomyx laboratories are about a ten-minute drive from Zuker’s lab, in a low-slung stucco building in Torrey Pines. Inside, about seventy-five scientists pursue what is known as “high-throughput screening”: a modern, hyper-accelerated version of Nofre and Tinti’s taste tests. They start by creating what they call artificial taste buds: human cells, with a single taste receptor, engineered with a fluorescent dye that lights up only when the receptor is triggered. The cells are placed in clear plastic trays divided into three hundred and eighty-four wells, each a couple of millimetres wide. A robotic arm with three hundred and eighty-four nozzles squirts a different compound into every well. Whenever a cell lights up–about a one-in-a-thousand occurrence–it is registered by a fluorometric sensor and tallied by a computer. In Nofre and Tinti’s days, testing this many samples would have taken months. At Senomyx, it takes less than five minutes.

“When you think about how many things have been tasted, it’s not that many,” Mark Zoller, the company’s head of research, told me. “Usually what people do is create derivatives of what they already know: if you have aspartame, you create neotame. We can go in completely from left field, with no preconceptions about what can be sweet. We have a library of two hundred and fifty thousand compounds, and we are creating new libraries all the time. We can throw it all at the receptor and let the results speak for themselves.” In the past four years, Senomyx has tested more than twenty million samples. Its sweetener program has identified the three most promising classes of chemicals, whittled those down to two candidates, and tinkered with them in the lab, adding some atoms for stability, some for potency. The final product won’t be a new sugar substitute–“How many of those do we need?” Zuker says. It may not even have any taste. All it will do is amplify the taste of sugar.

Taste potentiators, as they’re called, are not entirely new to the food industry. The ingredient list on a can of soup or a hunk of processed cheese sometimes includes a substance called IMP, a few entries below MSG, or monosodium glutamate. MSG is to umami what sugar is to sweet: the taste in its purest, most familiar form. IMP’s singular virtue is its synergy with MSG. Like the sweet receptor, the umami receptor has multiple binding sites. IMP attaches to one spot, MSG to another; together, they fit so snugly that their effect is multiplied. Add a little IMP to a soup with MSG in it, and the umami taste will increase roughly ten-fold. “It’s like a hearing aid,” Zoller told me. It turns up the volume.

Senomyx has found four new umami potentiators in the course of its chemical trawling, all of them more effective than IMP, all recently declared safe by the F.D.A. (The first products containing them should appear later this year.) The company’s two sweet potentiators aren’t quite as far along. The best one is known as Substance 951. If you add only a few parts per million of it to a soda, you can take out forty per cent of the sugar and the soda will taste as sweet. But Senomyx is still working on making it stronger and on improving or eliminating its taste. (I wasn’t allowed to try it.) Zoller says that the compound should be on the market by next year, but most consumers won’t be aware of it. Like the new umami potentiators, Substance 951 will be used in such tiny quantities that it won’t have to be listed on labels. Instead, it will join all the other “natural and artificial flavors” that float through our foods, ignored by all but the most obsessive ingredient-watchers, and quietly do the work that sugar once did.

Walking through the labs at Senomyx, watching taste cells turn on and off in their little plastic wells, I was reminded of a wooden display case that I’d seen at NutraSweet. The case was fitted with three glass vials, all with different sweeteners measured in portions of equal strength. The first vial held forty grams of sugar and was nearly full. The second had a thin layer of aspartame–about a fifth of a gram. The last was labelled “neotame” and looked empty. I had to hold it up to the light to see the faint glimmer of powder inside. You could call this progress. The sweeter the chemical, the fewer of its molecules will wind up in our bloodstreams. And, if that chemical can also help curb obesity and diabetes, so much the better. “We consume too many calories and we don’t have to,” Craig Petray told me. “If products can taste the same and have twenty-five or thirty per cent less sugar, that’s a start.”

The same argument, of course, has always been made for artificial sweeteners. Like the dream of the paperless office or the superhighway that will untangle traffic for good, it presumes that there is a natural limit to our needs–that humanity’s sweet tooth can be satisfied. Yet our sweet receptors evolved in environments with so little sugar that they may not have a shutoff point. Elizabeth Cashdan, an anthropologist at the University of Utah, has seen African bushmen pick fruit apart for the barest trace of pulp. “And honey! What they will go through for a taste of honey is just incredible,” she says.

A number of biologists have tried to gauge the depth of our appetite for sugar over the years. Newborns, they’ve found, are already fixated on sweetness. If you put some sugar on a latex nipple, an infant will suck it longer and harder than a plain nipple. Give her a drop of sweet water when she’s crying and her heartbeat will slow, her face will relax, and her brain activity will fall into a “hedonically positive” pattern. (Hugs and pacifiers have a similar effect, but not as lasting.) According to the biologist Julie Mennella, at the Monell Chemical Senses Center, sugar seems to trigger the release of opiates in the brain, both bringing pleasure and blocking pain. (When Mennella asked children to stick their hands in icy water, those with some sugar water in their mouths kept their hands in longer.) Adults who are offered drinks of different sugar concentrations tend to reach a “bliss point” at about nine teaspoons per cup–fifty per cent sweeter than the average soft drink. Children prefer eleven teaspoons per cup, and they’ll take it even stronger. “For babies, the fundamental rule is: the sweeter the better,” Monell’s director, Gary Beauchamp, told me. “There is nothing that is too sweet.”

Beauchamp has also tried to study the opposite tendency: the less sugar people eat, the less of a taste for it they have. He had to abandon the experiment, though, because his subjects couldn’t stick to their sugar-free diets. (They were much better at abstaining from salt; and he did find that their appetite for it diminished.) The human palate is nothing if not adaptable, but it’s hard to lose your craving for sugar when it’s found in everything from wheat bread to spaghetti sauce to macaroni and cheese. Artificial sweeteners, far from diminishing that appetite, often seem to reinforce it. Americans ate about twenty-four pounds of sugar substitutes per person last year, nearly double what they did in 1980, yet sugar consumption rose about twenty-five per cent in the same period. The trend is strongest among blacks and Hispanics–they like their food with about ten per cent more sugar than whites do, studies by Susan Schiffman, a medical psychologist at Duke, have shown–and weakest among Asians. As Schiffman puts it, our taste for sweeteners is being “upregulated.”

The closest analogy may be what has happened to our sense of pitch. In 1740, when Handel rang his tuning fork, an A above middle C had a frequency of four hundred and twenty-two hertz. Throughout the nineteenth century, orchestras were tuning it higher, straining to fill larger and larger halls and make their sound just a tittle more brilliant. These days, when Lorin Maazel rings his tuning fork, that same A gives a steady pitch of four hundred and forty hertz, but some conductors in Germany and Austria have gone up another five hertz. In music, if you go too high, strings snap and voices crack. In the matter of sweets, the only real limit is exhaustion: when Zuker offers sugar water to his mice, they keep on drinking until their tongues can hardly move.

One afternoon, Zuker drove me to an Asian strip mall a few miles from the university. A Chinese graduate student had recommended a place there called Spicy City. The restaurant had a bright-red carpet, devil masks and chili peppers on the walls, and a menu of daunting authenticity. Zuker glanced over the choices with a kind of sadomasochistic glee. “‘Hot spicy pork blood with black sea cucumber, squid, and golden mushroom,'” he said. “Is it kosher?” He finally settled on a dish called Husband and Wife, made of cold sliced beef and tripe drenched in chili oil. He liked to experience “very distinct, acute sensory events,” he explained. “The best is to eat something spicy, naked.”

Nothing in the biology of taste could really explain the appeal of Spicy City. Our tongues are wired for yes and no, good and bad, not for “It tastes like it’s rotting but I can’t stop eating it” or “It’s incinerating my flesh and I find this oddly pleasurable.” Any mouse knows to shun bitter and spicy foods as poisonous, but Zuker is no mouse. Like all of us, he is part rationalist and part sensualist–though perhaps he pushes both sides to an extreme. He has taken driving lessons at a racecar track, keeps a cellar full of Chilean wines, and built a swimming pool on the cliffs beside his house with a vanishing edge that seems to tumble into the void. The best part of being human, he knows, is ignoring what your body tells you from time to time.

The rise of sugar since Columbus sometimes seems destined to turn us all into lab animals, dutifully gorging on sweets. But Columbus did more than bring sugarcane to the New World. He also brought a few things home. Cocoa was popular long before it was sweetened, and chilies are now eaten by a quarter of the world’s adults every day. You can explain this in pharmacological terms (cocoa contains caffeine), in hygienic terms (chilies kill bacteria), or as a function of peer pressure. But the best explanation may be what the psychologist Paul Rozin, at the University of Pennsylvania, calls “benign masochism.” We eat chilies, Warheads, and bitter greens, and drink bitter tonics and bitter coffee, for the same reason that we ride roller coasters and watch horror films: to fool the body into thinking it’s in danger, and then enjoy the adrenal ride. Our taste buds may tell us that nothing is as good as sugar, but our minds can be taught to know better.

“We like to experience the edge, to push our sensory systems to the limit,” Zuker told me later, in his car. “Whether it’s tasting things or driving very fast cars, we like to enjoy things we should not enjoy.” He took a winding road down the coast, past a cluster of surfers in wetsuits paddling into the Pacific, and a pair of hang gliders getting ready to throw themselves from the cliffs of La Jolla. When the road peeled away from the shore, he shifted into third gear and accelerated to a hundred and fifteen, hurtling past a red truck that nearly turned into our lane. He glanced at me, backed deep into my seat with my hands clutching the armrests, and laughed. “You’re a pussy!” he shouted. Then he jammed the stick shift forward and threw the car into the next turn.

http://www.princeton.edu/~amoroz/2006/05/search-for-sweet.html

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