Xylitol toxicity in dogs. Is this tooth fairy medicine?

[malernee]

Safety

World Health Organization studies using much higher doses on dogs for long periods showed no ill effect.[33]


33. [1] Xlear, Inc. Issues Response to JAVMA Report on Dogs and Xylitol


here is a prospective study


Dog

Xylitol was administered in the diet of pure-bred beagle dogs
(eight male and eight female animals per group). Dietary concentration
of 0, 2, 5, 10 and 20% xylitol were attained by a gradual increase of
xylitol at the expense of starch. The 20% dietary level was reached by
the fifth week. A further group received 20% sucrose for comparative
purposes. Rice starch was included in the diets of groups receiving 0,
2, 5, and 10% xylitol, so that in each case the diet consisted of
80% normal diet and 20% carbohydrate. After week 42 diets were

supplemented with 5 ml corn oil (during weeks 42-48 once/day, week 48
onward once/week). After 52 weeks there was an interim sacrifice of
two males and two females per group. The study was terminated at 104
weeks.

The 20% xylitol and 20% sucrose groups left significantly more
food than the control group. The 2% xylitol group gained less weight
than controls. All other groups gained more weight than controls.
Haematological parameters and analysis were within normal limits
during the course of the study. Clinical chemistry studies showed that
from week 12 onwards slightly elevated total serum protein levels were
recorded in 20% xylitol group. Particularly in the first year, but
also in the second year, the 20% xylitol group had elevated SAP
values. At almost every interval, SGPT for 20% xylitol group was
elevated. In the second year this was also true for the 10% xylitol
group. Total LDH and alpha-HBDH showed considerable variation. During
weeks 89 and 100 the values for the 20% xylitol group were elevated.

At autopsy there was a significant increase in liver weight in
the 20% xylitol group. Changes in periportal hepatocytes were detected
histologically in at least five of 12 dogs in this group. Electron
micrographic analysis suggested that the changes in hepatocytes
observed were consistent with alterations in glycogen storage. No
evidence of degeneration or necrosis was noted. Similar histological
changes were found in the hapatocytes of three and 12 dogs in the 10%
sucrose group. No other compound-related changes were reported
(Heywood et al., 1977).



want to bet the ld50 for the dog using prospective trials turns out to be about 22000mg/kg?


Section 11: Toxicological Information
Routes of Entry: Inhalation.
Toxicity to Animals: Acute oral toxicity (LD50): 22000 mg/kg [Mouse].
Chronic Effects on Humans: The substance is toxic to lungs.
Other Toxic Effects on Humans:
Hazardous in case of inhalation.
Slightly hazardous in case of ingestion.
Special Remarks on Toxicity to Animals: Not available.




I wish there was a law that every vet who promoted "special dog toxins" had to put their home phone number on the paper so the people they needlessly frightened would call them not me. Seems like every month some vet has found a new dog toxin they want people to call their office about but it would not be a worry if their child of the same wt got into it.


We should limit strong advice to where randomized trials have proven a benefit. When you feel your veterinarian isn't doing enough to help protect your pet, don't stray from scientific healthcare in a desperate attempt to find a solution." Instead, ask your veterinarian to provide a more detailed explanation or to refer you to another doctor.


Prof David L. Sackett Director, Centre for Evidence-Based Medicine wrote


progress towards the truth is impaired in the presence of an expert

There are still far more experts around than is healthy

the point is well made that review articles, particularly those written by specialists, tend to be of dubious value, with authors selectively choosing evidence to support their own prejudices. I would argue, however, that most practicing clinicians know this already. The message is important, however, that expert reviews cannot be trusted. Sackett, often called the father of evidence based medicine, has always been wary of experts and has recommended that once a person has become an expert he or she should change jobs. This information has obviously filtered through to the "coal face" as clinicians are acting much more on primary data than filtered expert opinion. We should perhaps question why these expert reviews continue to be published, given both their lack of rigour and their apparent lack of influence.

[malernee]

my read is if xylitol elevates serum insulin the blood sugar will drop if the animal does not eat. Maybe dog owners should feed the dog rather than run it to the vet for eating sugarless chewing gum.


Effects on enzymes and other biochemical parameters

Xylitol has especially influence on the activity of the enzymes
of carbohydrates metabolism and the insulin hormone. Both in
experiments with parenteral and oral administration of xylitol a
stimulation of insulin secretion and an elevated serum insulin
concentration are observed in rat, dog and monkey, although the plasma
glucose level slightly increased for a while and then decreased below
the fasting level (Bässler and Prellwitz, 1964; Kuzuya et al., 1966,
1969; Hirata et al., 1967, 1968; Montague et al., 1967; Wilson and
Martin, 1970; Froesch, 1975; Jourdan et al., 1972; Touster, 1974).
Kuzuya et al. (1969) found that the insulin secretion produced by
xylitol in dogs was more pronounced than by glucose. Wilson and Martin
(1970) observed the same effect in dogs, while they found that in
monkeys glucose caused a more marked stimulation of the insulin
secretion than xylitol did. The insulin secretion in dogs is also much
stronger than in man (Hirata et al., 1967). Meng (1974) however did
not find any changes of the insulin level in dogs, i.v. infused with
xylitol. This study included only five animals.

[malernee]

Blood Glucose and Liver Function in Dogs Administered a Xylitol
Drinking Water Additive at Zero, One and Five times Dosage Rates
James M. G. Anthony, BSc (Ag), DVM, MRCVS, FAVD, Dip AVDC, Dip EVDC, PAg
Lynn P. Weber, BSc(Pharmacy), PhD(Pharmacology & Toxicology)
Stan Alkemade, BVSc, MRCVS
Summary:
A study was designed to determine the safety of a drinking water additive that reduces plaque and calculus in dogs, and contains
xylitol as an active ingredient. The randomized, double-blind, placebo-controlled study was performed in 15 crossbred dogs that
were randomly divided into three groups and had their drinking water treated for 14 days with either: a) a commercial health
care product (BreathaLyser Plus) at the recommended dosage, b) an experimental health care product (BreathaLyser Plus containing
five times the amount of xylitol), or c) a placebo of purified water with a colour additive. Results demonstrated that the
continuous administration of a commercial, drinking water, oral health product containing xylitol, at one and five times the normal
inclusion rate, does not cause hypoglycemia or alter liver function in dogs.
Introduction:
Xylitol is a five-carbon sugar alcohol that is used in a number of consumer products as a sweetener. The human consumption
of this product has increased over the past few years. In animals xylitol has proven to increase bone calcification, inhibit the
growth of certain bacteria and prevents oral bacteria from producing the acids that demineralize the tooth surface.1,2,
There have been reports that dogs may develop mild to severe insulin induced hypoglycemia after ingesting products containing
xylitol.3,4,5 Xylitol has little or no effect on plasma insulin or glucose level in humans, yet in dogs, xylitol increases insulin
release and can cause severe hypoglycemia with ataxia, collapse and seizures.3 Although xylitol is absorbed slowly in humans,
it is rapidly and almost fully absorbed in dogs, with peak plasma concentration occurring within 30 minutes.6 Additionally, there
have been reports that dogs may develop acute hepatic failure following xylitol ingestion.7
Therefore, since there is concerns regarding the safety of administering oral dental care products containing xylitol
(BreathaLyser Plus) a study examining the toxicity in dogs is needed. To prove the safety of this product a 14 day oral toxicity
study was conducted in dogs at the usual and a 5 times the recommended dosage in the Animal Research Centre at the Western
College of Veterinary Medicine, Saskatoon, Saskatchewan.
Materials and Methods:
A randomized, double blind, placebo controlled study was performed where fifteen crossbred dogs of mixed ages (mean years:
3.1, range 2-7 years), weight (mean kg: 24.8, range 16-40) and sex (females: 8, males: 7) were randomly divided into three
groups and their drinking water was treated for 14 days with either: a) commercial care product (BreathaLyser Plus, imRex Inc.,
London, ON, Canada), b) BreathaLyser Plus containing five times the amount of xylitol recommended by the manufacturer, or
c) placebo (purified water coloured to match solutions (a) and (b)). At the start of the study, there were no differences between
the three groups for breed, sex, age, or weight. Throughout the trial, all dogs were maintained in the same environment and fed
the same commercial dog food (Iams Adult, Iams Company, Dayton, Ohio, USA). No food supplementations such as treats or
chew toys were given during the study.
All dogs in this study were examined for general health and acclimatized to the facilities for eight days before entering the study.
On day 0, samples for complete blood count, and clinical chemistry (Na, K, Na:K ratio, Cl, HCO3, Anion Gap, Ca, P, Mg, Urea,
Creatinine, Glucose, Total Bilirubin, Cholesterol, AP, ALT, GGT, GLDH, CK, Total Protein Albumin, Globulin, A:G Ration,
SDH) were collected at approximately seven hours after feeding. All samples were performed at an independent diagnostic laboratory
(Prairie Diagnostic Services, Saskatoon, Saskatchewan). Each study group was then placed on drinking water containing
the appropriate test product and maintained on the treated water for 24 hours per day for 14 days. The principal investigator
and all study and laboratory personnel were blind as to which test article was being administered to each group. Prior to
feeding on the following day, each animal had blood collected for glucose analysis. Animals were fed and subsequent blood
samples for glucose were obtained at two-hour intervals for a total of four samples for each animal. The animals were observed
throughout the study period for any adverse effects or behavioral changes. On the last day of the study (day 14), blood samples
were once again collected for complete blood count and blood chemistry at approximately seven hours after feeding, and the
dogs were then returned to normal drinking water. Data are expressed as mean ± standard error of the mean (SEM). Differences
among treatment were tested using repeated measures analysis of variance (ANOVA) followed by Tukey’s posteriori test, as
appropriate. Differences were considered to be significantly different if p<0.05.
Results:
All dogs freely accepted and drank the water with the study additives. Throughout the study there were no noteworthy abnormal
findings for CBC or clinical blood chemistry. No adverse events were observed or reported. All glucose samples from all
treatment groups were within the normal range during the entire study (Fig. 1). Blood glucose showed a diel variation in all treatment
groups on the first day of treatment, with blood glucose in the lower end of the normal range in the morning sample taken
before feeding the dogs (Fig. 1). The blood glucose then rose as the dogs fed throughout the rest of the day, but without any difference
detected among treatment groups (Fig.1). However, there was a minor, but statistically significant increase in blood glucose
at day 14 in the dogs from the 5 times treated group compared to the control group (Fig. 1). Analyses of liver function tests
(AP, ALT, GGT) demonstrated no significant effect of xylitol treatment at any time during the study (Table 1).
Discussion:
Xylitol is a five-carbon sugar alcohol or pentitol that is mainly used as an artificial sweetener is a variety of human consumer
products, such as sugar free chewing gum and baked goods. In animals (dogs and cats), xylitol is being used in some oral care
products. Xylitol has an antibacterial effect on oral bacteria, especially on plaque, and decreases the formation and accumulation
of calculus on the tooth.8,9,10,11
Oral xylitol has a wide margin of safety in most animal species.5 There have been reports in the litature that dogs may develop
mild to severe insulin induced hypoglycemia after ingesting products containing xylitol.3,4,5,6,7 It has been suggested that
dogs fed 0.1 g/kg xylitol could develop hypoglycemia.7 This theory is based on the observation that dogs given intravenous
xylitol demonstrated a dose dependant release of insulin that resulted in a concurrent drop in blood glucose.6,12,13 After a toxic
dose of xylitol is ingested by dogs, the initial sign is vomiting, followed by lethargy, ataxia, collapse, and seizures.7
Hypoglycemia with hypokalemia (insulin causes potassium to move into cells with the glucose) and hypophosphatemia (insulin
can increase cellular permeability to phosphate ions) is the physiological outcome.5 Additionally, acute liver failure has been
reported in dogs consuming a single large dose of xylitol; resulting in elevated liver enzymes: alanine transaminase (high),
bilirubin (mild to moderate elevation), and alkaline phosphatase (mild).7 Thus, it is hypothesized, that a xylitol oral dosage of
greater than 0.1 g/kg can result in clinical sign of hypoglycemia and a dosage greater than 0.5 g/kg can be hepatotoxic.5 We
hypothesize that at the recommended dosage of BreathaLyser Plus and at 5 times its dosage rate will not produce hepatotoxicity
or hypoglycemia.
This study of blood glucose and liver function in dogs administered a xylitol product at zero, one and five times dosage rates
significantly demonstrated that BreathaLyser Plus is safe product even at five times the dosage rate in dogs.
BreathaLyser Plus contains xylitol as an active ingredient. It is supplied as a concentrate which, when diluted according to the
directions, produce drinking water containing 0.05mg/mL of xylitol. Healthy dogs consume 20-70 mL/kg/day of water,
depending on the environmental temperature, physical activity, and whether they are fed moist or dry foods.14 A maximum
intake of xylitol of 3.5 mg/kg at the recommended dosage and 17.5 mg/kg at five times the dosage would be consumed daily
by each dog. Because the total daily water intake is not consumed at one time, the actual safety margins would be much higher.
The current study of basic blood chemistry, blood glucose and liver function in dogs administered a xylitol product at 1 times
and 5 times dosage demonstrated that BreathaLyser Plus is not hepatotoxic and does not cause hypoglycemia in dogs. In fact,
the significant elevation in blood glucose at day 14 in the 5 times dosage group suggests that BreathaLyser Plus may in fact
cause hyperglycemia, not hypoglycemia. However, it is important to note that the blood glucose at this time, even though elevated,
is still within the normal range. Therefore, based on the results of this study, BreathaLyser Plus is a safe product even at
5 times the dosage rate in dogs.
BreathaLyser Plus, imRex Ltd., London, Ontario, Canada
Iams Company, Dayton, Ohio, USA
Author Information:
James M.G. Anthony, Dept SACS, WCVM, University of Saskatchewan, 52 Campus Drive, Saskatoon, Saskatchewan,
Canada, S7N 5B4
Lynn P. Weber, Veterinary Biomedical Sciences, University of Saskatchewan, 52 Campus Drive, Saskatoon, Saskatchewan,
Canada, S7N 5B4
Stan Alkemade, Worldwide BioMedEx Inc., 12801 Medway Road, Arva, Ontario, Canada, N0M 1C0
References:
1 Cronin JR. Xylitol: a sweet for healthy teeth and more. Alternative Complementary Therapy 2003; 9: 139-141.
2 Gare F. The sweet miracle of xylitol. North Bergan, NJ: Basic Health Publications Inc, 2003.
3 Dunayer EK. Hypoglycemia following canine ingestion of xylitol containing gum. Vet Human Toxicology 2004; 46 (2): 87-88.
4 Foss TS. Xylitol: sweet temptation for dogs. Vet Technician 2004; Nov: 773-775.
5 Dunayer EK. New findings on the effects of xylitol ingestion in dogs. Vet Medicine 2006; Dec: 791-796.
6 Kuzuya T, Kanazawa Y, Kosaka K. Stimulation of insulin secretion by xylitol in dogs. Endocrinology 1969; 84: 200-207.
7 Dunayer EK, Gwaltney-Brant SM. Acute hepatic failure and coagulopathy associated with xylitol ingestion in eight dogs. J
American Vet Med Association 2006; Oct 1: 229(7): 1113-1117.
8 Tranan L. Xylitol: a review of its actions on mutans streptococci and dental plaque- its clinical significance. Int Dent J 1995;
45: 77-92.
9 Waler SM, Rolla G, Assev S, Clardi JE. The effect of xylitol on plaque metabolism. Swed Dent J 1984; 8: 155-161.
10 Makinen KK. New biochemical aspects of sweeteners. Int Dent J 1995; 35: 23-35.
11 Clarke DE. Drinking water additive decreases plaque and calculus accumulation in cats. J Vet Dent 2006; June: 23(2): 79-82.
12 Kuzuya T, Kanazawa Y, Kosaka K. Plasma insulin response to intravenously administered xylitol in dogs. Metabolism 1966;
15: 1149-1152.
13 Hirata Y, Fujisawa M, Sato H, et al. Blood glucose and plasma insulin responses to xylitol administered intravenously in dogs.
Biophy Res Commun 1966; 24: 471-475.
14 Nelson RW. Polyuria, polydipsia and diabetes insipidus. Proc ACVIM, 27th WSAVA Congress. Granada, ES. 2002.
Table 1. Serum enzyme activities (U/L) in dogs (n = 5 dogs per group) given normal tap water treated with a
blue dye (control), water with the recommended dose of Breathalyzer Plus (1x Dose) or water with
Breathalyzer formulated to containing 5x xylitol (5x Dose) for 14 days. Blood samples were taken from dogs
one day before exposure (Day 0) and at the end of the exposure (Day 14). Results are shown as mean ± SEM.
No significant effects of treatment were detected using a one-way repeated measure ANOVA.
Figure 1. Blood glucose levels determined in dogs (n = 5 dogs per group) given normal tap water treated with
a blue dye (control), water with the recommended dose of BreathaLyzer Plus (1x Dose) or water with
Breathalyzer formulated to containing 5x xylitol (5x Dose) for 14 days. Blood samples were taken from dogs
one day before exposure (Day 0), at four time-points during the first day of exposure (Day 1 – T0, Day 1 – T1,
Day 1 – T2 and Day 1 – T3) and at the end of the exposure (Day 14). Results are shown as mean ± SEM.
Significant overall effects of treatment (p=0.01) and time/day of blood collection (p<0.0005) were detected
using a two-way ANOVA. **p<0.01, ***p<0.001 compared to Day 0 value within the same treatment group
and #p<0.05 compared to control values at the same time point in Tukey’s posteriori tests

[malernee]

Xlear, Inc. Issues Response to JAVMA Report on Dogs and Xylitol
Market Wire, October, 2006
12Next
Xlear, Inc., a leading manufacturer of xylitol products, issued the following statement in response to the clinical report on xylitol and dogs published in the October 1, 2006 issue of the Journal of the American Veterinary Medical Association (JAVMA).

Reports and articles about xylitol and dogs have propagated across the Internet during the past several months. While Xlear does not manufacture xylitol products for pets, nor recommend giving xylitol to dogs, we feel that there have been some misconceptions reported in recent papers and statements about xylitol that need to be addressed.

First, xylitol has been used in a number of animal studies and the results of which have been included in the World Health Organization's review of the safety and toxicology of xylitol. In several of the studies, up to 20 percent of the total caloric intake for dogs was comprised of xylitol. These studies were conducted during a full-year time period, and after the study, the animals were sacrificed and histology studies conducted on their organs. No abnormalities were noted. Other studies have also shown xylitol to be safe. Please see the following:

-- http://www.inchem.org/documents/jecfa/j ... 12je22.htm

-- http://www.inchem.org/documents/jecfa/j ... 13je11.htm