MICROgenics Glucosamine Plus Joint Formula by Sanofi-Aventis Australia

LIKELY EFFECTIVE

• Boron deficiency. Oral boron treats and prevents boron deficiency. Details: Taking boron orally is effective for preventing and treating boron deficiency (7135).

POSSIBLY EFFECTIVE

• Radiation dermatitis. Topical application of sodium pentaborate pentahydrate gel to radiation sites may reduce the risk of dermatitis in patients with breast cancer who are receiving radiotherapy. Details: A small clinical study in patients with breast cancer shows that applying a hydrogel containing sodium pentaborate pentahydrate 3% four times daily during radiotherapy for 5 weeks reduces the risk of moderate to severe dermatitis by 50% when compared with petroleum jelly (Vaseline). However, there is no difference in patient satisfaction (95660). Additionally, a larger clinical trial in patients with breast cancer shows that applying a sodium pentaborate pentahydrate 3% gel to radiation sites 15 minutes before each session for 25 sessions reduces the risk of dermatitis by 90%, erythema by 87%, dry desquamation by 92%, and moist desquamation by 97% when compared with a placebo gel (109557).
• Vaginal candidiasis. Boric acid applied intravaginally seems to reduce vaginal candidiasis. Details: Some limited clinical research shows that applying boric acid powder intravaginally 600 mg once or twice daily for up to 3 weeks can treat candidiasis and other vaginal fungal infections, including resistant and chronic infections (15443,15444,15446,15449,15450,15451,15453); however, this research is limited by low study quality. For Candida glabrata yeast infections, which are less prevalent than Candida albicans infections, some evidence shows that intravaginal boric acid capsules are effective in about 65% to 70% of azole-resistant infections; however, boric acid capsules appear to be less effective than intravaginal flucytosine (Ancobon) (15445,15454). For Candida krusei infections, which are rare and resistant to azole antifungal treatment, boric acid capsules also appear to be effective in some cases (15448).

POSSIBLY INEFFECTIVE

• Athletic performance. Oral boron does not seem to improve athletic performance. Details: A small clinical study in male bodybuilders shows that taking boron 2.5 mg daily for 7 weeks does not increase lean body mass, muscle mass, or testosterone levels when compared with placebo (944). Furthermore, the International Society of Sports Nutrition (ISSN) does not recommend boron supplementation as a nutritional ergogenic aid due to a lack of supportive evidence (101009).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral boron is beneficial for age-related cognitive decline. Details: Two very small clinical studies in healthy older adults show that taking boron 3.25 mg daily for up to 49 days orally might improve cognitive function and fine motor skills when compared with lower amounts of boron (943).
• Diabetic foot ulcers. It is unclear if topical boron is beneficial for use in diabetic foot ulcers. Details: A large clinical study in adults with diabetic foot ulcers shows that applying boron (sodium pentaborate 3%) gel twice daily for 1 month marginally reduces ulcer severity, measured by the Wagner Classification system at 25 days and 2 months, when compared with control; recurrence and infection rate were also modestly reduced at 2 months (112423). However, it is unclear whether the analysis controlled for systemic antibiotic use among the two groups, which effects the validity of these findings.
• Dysmenorrhea. It is unclear if oral boron is beneficial for reducing pain during menstruation. Details: A small clinical study in young females with moderate to severe dysmenorrhea suggests that taking boron tetraborate 10 mg daily, starting two days before and continuing until three days after the start of menstruation for two menstrual cycles, reduces pain levels by 24% and pain duration by 1.5 hours, or 34%. Both pain and pain duration were decreased by only 9% in patients receiving placebo (95428).
• Kidney stones (nephrolithiasis). It is unclear if boron is beneficial for medical expulsive therapy after extracorporeal shockwave lithotripsy. Details: A large clinical study in adults undergoing extracorporeal shockwave lithotripsy for kidney stones conducted in Iran shows that taking boron 10 mg twice daily for 2 weeks does not statistically improve the rate of stone expulsion when compared with tamsulosin; however, boron may have fewer side effects (i.e., orthostatic hypotension, headache, nausea, erectile dysfunction) (112414).
• Kidney transplant. It is unclear if oral boron is beneficial in patients receiving a kidney transplant. Details: Observational research in kidney transplant recipients has found that higher boron intake, as measured by urinary boron levels, is associated with a lower risk of mortality when compared with lower intake. Patients with 24-hour urinary boron levels in the top tertile had a 49% lower risk of all-cause mortality when compared with those in the lowest tertile; however, there was no association with graft failure (109556). It is unclear if these findings can be generalized to boron supplements.
• Obesity. Although there has been interest in using oral boron for obesity, there is insufficient reliable information about the clinical effects of boron for this purpose.
• Osteoarthritis. It is unclear if oral boron is beneficial for osteoarthritis symptoms. Details: Small low quality studies in patients with osteoarthritis suggest that taking boron tetraborate 3-6 mg daily for up to 8 weeks might improve pain and other symptoms when compared with a lower intake of boron (941,36870).
• Osteoporosis. It is unclear if oral boron is beneficial for osteoporosis. Details: Preliminary clinical research in postmenopausal adults shows that taking boron 3 mg daily does not improve bone density when compared with placebo (36872).
• Periodontitis. Small clinical studies suggest that adding topical boric acid to scaling and root planing treatment may be beneficial in periodontitis. Details: A meta-analysis of four small clinical studies in 117 patients with periodontitis shows that using boric acid 0.75% gel or solution in addition to scaling and root planing seems to slightly improve probing pocket depth (PPD) and clinical attachment level (CAL) when compared with placebo or saline control (105690). Another small clinical study in patients with periodontitis shows that using boric acid 0.5% for irrigation in addition to scaling and root planing seems to improve CAL and PPD to a similar degree as using povidone-iodine 0.1% (105691). The available research was conducted in Turkey, Vietnam, and India; it is unknown if these findings are generalizable to other geographic locations.
• Tooth extraction. It is unclear if boron is beneficial for use in periodontal healing after impacted third molar surgery. Details: A moderate-sized clinical study in adults 18 to 40 years old shows that using boron 0.1% to 2.5% and chlorhexidine 0.12% mouthwash for 7 days after impacted third molar surgery marginally improves swelling and self-reported pain on day 7, and the higher boron concentrations also improve pain at day 4 when compared with chlorhexidine alone, but does not improve the number of analgesics used or periodontal scores (112379). However, the validity of these results is limited by a lack of statistical adjustment for multiple comparisons which can lead studies to show differences between treatment groups in error (i.e., false positive findings). Additionally, the study period coincides with the expected recovery time (i.e., 2-7 days), making it unclear if any effects are due to the intervention or control. More evidence is needed to rate boron for these uses.

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LIKELY EFFECTIVE

• Copper deficiency. Oral or intravenous copper is beneficial for treatment of copper deficiency. Details: Taking copper orally or intravenously is effective for treating copper deficiency and anemia due to copper deficiency. Copper deficiency is rare. It is seen most commonly in people receiving prolonged parenteral nutrition (7135). Oral cupric sulfate has been used in doses up to 0.1 mg/kg daily (7135). Copper 1-2 mg per day in parenteral nutrition solution has also been used (505).

POSSIBLY INEFFECTIVE

• Alzheimer disease. Oral copper does not seem to be beneficial for Alzheimer disease. Details: Preliminary clinical research shows that taking copper orotate dihydrate, providing 8 mg of elemental copper, daily for 12 months does not improve scores on evaluation scales for Alzheimer disease when compared with placebo (45949). There is also some concern that copper could have detrimental effects. Observational research has found that people with Alzheimer disease have higher levels of copper in their blood than people without the disease (95917); the clinical significance of this finding is unclear.

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Acne. Oral copper has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Preliminary clinical research shows that taking a specific combination product containing copper (NicAzel, Elorac Inc.) 1-4 tablets daily for 8 weeks reduces inflammatory lesions in patients with inflammatory acne when compared with baseline. Other ingredients in this product include nicotinamide, azelaic acid, zinc, pyridoxine, and folic acid; specific quantities are not known (90800). The validity of this finding is limited by the lack of a comparator group.
• Brain tumor. It is unclear if oral copper is beneficial for use in glioblastoma. Details: A moderate-sized open-label clinical study in adults with first recurrence of glioblastoma receiving alkylating chemotherapy shows that taking elemental copper 2.5 mg with disulfiram 400 mg daily for 6 months does not improve survival but does result in significantly more adverse effects (e.g., elevated liver enzymes) when compared with control. The trial was stopped early due to safety concerns (112376).
• Cardiovascular disease (CVD). Although there is interest in using oral copper for CVD prevention, there is insufficient reliable information about the clinical effects of copper for this purpose.
• Chemotherapy-induced acral erythema. Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months may reduce the incidence of grades 3 and 4 acral erythema (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Chemotherapy-induced anemia. Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months does not appear to reduce the incidence of grades 3 and 4 anemia (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Chemotherapy-induced diarrhea. Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months may reduce the incidence of grades 3 and 4 diarrhea (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Chemotherapy-induced leukopenia. Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months does not appear to reduce the incidence of grades 3 and 4 neutropenia or febrile neutropenia (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Chemotherapy-induced nausea and vomiting (CINV). Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months may reduce the incidence of grades 3 and 4 vomiting (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Chronic venous insufficiency (CVI). It is unclear if compression stockings containing copper are beneficial for lipodermatosclerosis in patients with CVI. Details: Preliminary clinical research shows that using compression stockings impregnated with copper for 8 weeks does not improve overall symptoms of lipodermatosclerosis secondary to chronic venous disease when compared with using a compression stocking without copper. However, the affected surface area may be reduced by approximately 16% by 2 weeks when copper-impregnated compression stockings are used (101809).
• Dental plaque. It is unclear if rinsing the mouth with copper is beneficial for reducing dental plaque. Details: Preliminary clinical research shows that rinsing the mouth with a solution of copper 1.1 mmol/L for 4 days decreases plaque accumulation when compared with a placebo solution (46006).
• Diarrhea. Oral copper has only been evaluated in combination with zinc; its effect when used alone is unclear. Details: Preliminary clinical research in children 6 months to 5 years of age presenting to a hospital in India with acute watery or bloody diarrhea shows that taking a solution providing zinc 2 mg/kg and copper 0.2 mg/kg orally daily for 2 weeks does not reduce the duration of diarrhea, the weight of stool, or the need for rehydration when compared with placebo (87166). It also does not seem to reduce the recurrence of diarrhea or improve weight gain over the next 3 months (95540).
• Oral mucositis. Oral copper has only been evaluated in combination with resveratrol; its effect when used alone is unclear. Details: A small clinical study in adults with advanced gastric cancers receiving docetaxel-based chemotherapy suggests that taking copper (Chelated Copper, JR Carlson Laboratories, LLC) with resveratrol three times daily for up to 6 months may reduce the incidence of grades 3 and 4 oral mucositis (112377). However, the interpretation of these findings is limited by the lack of a control group.
• Osteoarthritis. Although there is interest in using topical copper for osteoarthritis, there is insufficient reliable information about the clinical effects of copper for this condition.
• Osteoporosis. Oral copper has only been evaluated in combination with other minerals; its effect when used alone is unclear. Details: Preliminary clinical research in postmenopausal adults shows that taking copper 2.5 mg in combination with zinc 15 mg, manganese 5 mg, and calcium 1000 mg daily for 2 years can slow bone loss when compared with taking either calcium or the trace minerals alone (1994).
• Postoperative infection. It is unclear if copper-impregnated wound dressings are beneficial for the prevention of postoperative infection. Details: Preliminary clinical research shows that using a wound dressing impregnated with copper oxide 3% by weight reduces the incidence of a surgical site infection in the 30-day period following a caesarean section by 39%, but does not reduce length of hospital stay or readmission rate, when compared with a non-copper wound dressing. Eight patients would need to be treated with the copper-impregnated dressing to prevent one infection (105363). This study is limited by the use of a telephone questionnaire to assess the suspicion of infection.
• Systemic lupus erythematosus (SLE). It is unclear if oral copper is beneficial for improving symptoms of SLE. Details: Copper status does not appear to be associated with the risk of SLE (101810). Additionally, one small clinical study shows that taking copper 3 mg daily, alone or in combination with fish oil, for 24 weeks does not affect symptoms of SLE when compared with placebo (12953).
• Tinea pedis. Although there is interest in using topical copper for tinea pedis, there is insufficient reliable information about the clinical effects of copper for this condition.
• Wound healing. It is unclear if topical copper sulfate can improve the healing of umbilical granuloma. Details: A small clinical study in children 1-3 months of age with treatment-naïve umbilical granuloma shows that a single application of copper sulfate to the affected site results in complete resolution in 70% of patients, compared with 90% of patients receiving topical sodium chloride twice daily for 5 days. Some patients who received a second application of copper sulfate experienced full healing; however, it is unclear if this was due to the treatment or natural resolution (109403). More evidence is needed to rate copper for these uses.

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EFFECTIVE

• Manganese deficiency. Oral and intravenous manganese can prevent and treat manganese deficiency. Details: Taking manganese orally or intravenously is effective for preventing or treating manganese deficiency (15). However, the incidence of manganese deficiency is not well documented. Long-term home parenteral nutrition should provide no more than 55 mcg daily of manganese for adults or 1 mcg/kg daily (up to 50 mcg) of manganese for children unless clinically indicated (96416,99302). A clinical trial in children aged 8-14 months who are manganese deficient shows that taking manganese in addition to other vitamins and minerals in a 30 mL beverage six days per week for up to 14 months promotes growth when compared with placebo (19348).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Allergic rhinitis (hay fever). It is unclear if intranasal manganese is beneficial in patients with allergic rhinitis. Details: A small clinical study in patients with chronic allergic rhinitis shows that using an isotonic seawater nasal spray enriched with manganese (Sterimar Mn, Laboratori Baldacci) four puffs daily for 5 months, in addition to standard treatment with oral antihistamines, nasal corticosteroids, and nasal decongestants, reduces the number of acute exacerbations by about three when compared with the standard treatment alone (99416). However, the effect of the manganese in this product is unclear since nasal lavage with a plain saline nasal spray also helps in allergic rhinitis.
• Chronic obstructive pulmonary disease (COPD). Intravenous manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in patients being treated for exacerbation of COPD shows that intravenous supplementation with manganese 0.4 mg, selenium 100 mcg, and zinc 2 mg daily may shorten the number of days spent on mechanical ventilation when compared with placebo (61432). It is unclear if these findings are due to manganese, other ingredients, or the combination.
• Metabolic syndrome. It is unclear if oral intake of or environmental exposure to manganese decreases the risk of metabolic syndrome. Details: A meta-analysis of 12 observational studies suggests that increased dietary intake of manganese or higher levels of manganese in the serum, whole blood, or urine are not associated with a lower risk of metabolic syndrome when compared with lower manganese intake or laboratory values (112138).
• Obesity. Oral manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in overweight adults shows that taking a specific combination product (7-Keto Naturalean, Enzymatic Therapy, Inc.) containing manganese 500 mcg, 7-oxo-DHEA 100 mg, L-tyrosine 100 mg, asparagus root extract 100 mg, choline bitartrate 50 mg, inositol 50 mg, copper gluconate 500 mcg, and potassium iodide 100 mcg daily for 8 weeks reduces body weight by around 1.5 kg and body mass index (BMI) by around 0.7 kg/m² when compared with placebo (61581).
• Osteoarthritis. Oral manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Small clinical studies in patients with osteoarthritis of the knee and lower back show that taking a specific combination product (Cosamin DS, Nutramax Laboratories) containing manganese ascorbate 228-304 mg (about 31-41 mg of elemental manganese), glucosamine hydrochloride 1500-2000 mg, and chondroitin sulfate 1200-1600 mg daily for 4 months improves pain and ability to do activities of daily living when compared with baseline or placebo (4237,7169). The amount of manganese in the Cosamin DS formulation used in this study is considerably higher than the 1 mg of elemental manganese per 1500 mg of glucosamine hydrochloride in the current formulation. Since numerous studies show glucosamine with chondroitin without manganese might be effective for osteoarthritis, it is not possible to draw conclusions about the effects of manganese alone.
• Osteoporosis. Oral manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in postmenopausal patients shows that taking manganese 5 mg in combination with elemental calcium 1000 mg, zinc 15 mg, and copper 2.5 mg daily for 2 years reduces spinal bone loss when compared with placebo (1994). Another small clinical study in females with osteopenia shows that taking a specific combination product (Vitrum Osteomag, Unipharm Inc.) containing manganese 1.8 mg, calcium 600 mg, vitamin D (cholecalciferol) 200 IU, magnesium 40 mg, zinc 7.5 mg, copper 1 mg, and boron 250 mcg twice daily for one year improves bone mineral density when compared with no treatment (36840). However, since numerous studies have demonstrated the efficacy of calcium plus vitamin D for osteoporosis, it is not possible to draw conclusions about the effects of manganese alone.
• Premenstrual syndrome (PMS). Oral manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A very small clinical study in patients with PMS shows that taking manganese 1.0 mg or 5.6 mg in combination with calcium 587 mg or 1336 mg daily for about 24 weeks improves symptoms of PMS including pain, crying, loneliness, anxiety, restlessness, irritability, mood swings, depression, and tension (2004).
• Wound healing. Topical manganese has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Observational research has found that applying an alginate dressing containing manganese, calcium, and zinc to chronic wounds for 12 weeks is associated with improved wound healing when compared with previous treatments (61327). It is unclear if these findings are due to manganese, other ingredients, or the combination. More evidence is needed to rate manganese for these uses.

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LIKELY SAFE ...when used orally and appropriately. Boron is safe in amounts that do not exceed the tolerable upper intake level (UL) 20 mg daily (7135). ...when used vaginally. Boric acid, the most common form of boron, has been safely used for up to six months (15443,15444,15445,15446,15458,15449,15451,15453,15454). ...when used topically. Boron, in the form of sodium pentaborate pentahydrate 3% gel, has been applied to the skin with apparent safety up to four times daily for up to 5 weeks (95660,109557).

POSSIBLY UNSAFE ...when used orally in doses exceeding the UL of 20 mg daily. Higher doses might adversely affect the testes and male fertility (7135). Poisoning has occurred after ingestion of boron 2.12 grams daily for 3-4 weeks (17). Death has occurred after ingesting a single dose of 30 grams (36848,36863).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Boron is safe in amounts that do not exceed the tolerable upper intake level (UL). The UL by age is 3 mg daily at 1-3 years, 6 mg daily at 4-8 years, 11 mg daily at 9-13 years, and 17 mg daily at 14 years or older (7135). The UL for infants has not been determined (7135).

CHILDREN: POSSIBLY UNSAFE
when used orally in doses exceeding the age-based UL (7135). ...when applied topically in large quantities. Infant deaths have occurred after the use of topical boric acid powder to prevent diaper rash (36873,36874).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Boron is safe in amounts that do not exceed the UL during pregnancy or lactation, which is 20 mg daily in those 19-50 years of age or 17 mg daily for those 14-18 years of age (7135).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in doses exceeding the UL. Higher doses might impair growth and cause adverse effects in the developing fetus (7135,102058). ...when used vaginally. Intravaginal boric acid has been associated with a 2.7- to 2.8-fold increased risk of birth defects when used during the first 4 months of pregnancy (15443,15645).

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LIKELY SAFE ...when used orally and appropriately. Copper is safe in amounts that do not exceed the tolerable upper intake level (UL) of 10 mg daily (7135).

POSSIBLY SAFE ...when copper oxide is used topically. A wound dressing impregnated with copper oxide in concentrations of 3% by weight has been used with apparent safety in one clinical trial (105363).

POSSIBLY UNSAFE ...when used orally in doses exceeding the UL of 10 mg daily. Higher intake can cause liver damage (7135,45865). Kidney failure and death can occur with ingestion of as little as 1 gram of copper sulfate (17).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Copper is safe in amounts that do not exceed the tolerable upper intake level (UL) of 1 mg daily for 1-3 years of age, 3 mg daily for 4-8 years of age, 5 mg daily for 9-13 years of age, and 8 mg daily for 14-18 years of age (7135).

CHILDREN: POSSIBLY UNSAFE
when used orally in doses exceeding the UL (7135). Higher intake can cause liver damage (7135).

PREGNANCY: LIKELY SAFE
when used orally and appropriately. Copper is safe in amounts that do not exceed the tolerable upper intake level (UL) of 8 mg daily for those 14-18 years of age or 10 mg daily for those 19 years and older (7135).

PREGNANCY: POSSIBLY UNSAFE
when used orally in doses exceeding the UL. Higher intake can cause liver damage (7135).

LACTATION: LIKELY SAFE
when used orally and appropriately. Copper is safe in amounts that do not exceed the tolerable upper intake level (UL) of 8 mg daily for those 14-18 years of age or 10 mg daily for those 19 years and older (7135).

LACTATION: POSSIBLY UNSAFE
when used orally in doses exceeding the UL. Higher intake can cause liver damage (7135).

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LIKELY SAFE ...when used orally and appropriately. Oral manganese is safe when used in doses below the tolerable upper intake level (UL) of 11 mg daily for adults 19 years and older (1994,7135). ...when used parenterally and appropriately. Parenteral manganese chloride and manganese sulfate are FDA-approved prescription products.

POSSIBLY UNSAFE ...when used orally in high doses. Doses exceeding 11 mg daily can cause significant adverse effects (7135). ...when used parenterally in moderate or high doses, long-term. Reports of neurotoxicity and Parkinson-like symptoms have been reported with parenteral nutrition manganese doses above 60 mcg daily. It is recommended that adults on long-term parenteral nutrition receive manganese in doses of no more than 55 mcg daily (99302).

LIKELY UNSAFE ...when inhaled in moderate doses, long-term. According to the US Occupational Safety and Health Administration (OSHA), the permissible exposure limit (PEL) for manganese is 5 mg/m3. Exposure to higher amounts of manganese dust or fumes has been associated with central nervous system toxicity, Parkinson-like symptoms, and poor bone health (61296,102516).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Manganese is safe in children when used in daily doses less than the tolerable upper intake level (UL) of 2 mg in children 1-3 years, 3 mg in children 4-8 years, 6 mg in children 9-13 years, and 9 mg in children 14-18 years (7135).

CHILDREN: POSSIBLY UNSAFE
when used orally in excessive doses. Daily doses greater than the UL are associated with a greater risk of toxicity (7135).

CHILDREN: LIKELY UNSAFE
when inhaled at moderate doses, long-term. Exposure to high amounts of manganese dust has been associated with central nervous system toxicity and Parkinson-like symptoms (61296).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Manganese is safe when used in doses below the tolerable upper intake level (UL) of 11 mg daily during pregnancy or lactation in those aged 19 or older. However, those under 19 years of age should limit doses to less than 9 mg daily (7135).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses. Doses over the UL are associated with a greater risk of toxicity (7135). Additionally, observational research shows that adults with higher blood manganese levels have greater odds of delivering low birth weight or small for gestational age (SGA) male, but not female, infants (102515).

PREGNANCY AND LACTATION: LIKELY UNSAFE
when inhaled at moderate doses, long-term. Manganese salts can cross the placenta, and animal research suggests that large amounts of manganese may be teratogenic (61296).

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CONTRACEPTIVE DRUGS Interaction Rating = Minor Be watchful with this combination. Severity = Mild •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking copper with contraceptive drugs might increase the levels and toxic effects of copper.  Details A meta-analysis of clinical studies suggests that chronic use of oral contraceptives increases serum copper levels by a mean of 57 mcg/dL. In most people, this resulted in levels above the normal reference range for copper (92395).

PENICILLAMINE (Cuprimine, Depen) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, taking copper with penicillamine might decrease the absorption of penicillamine; separate dosing by at least 2 hours.  Details Copper chelates penicillamine, which decreases its absorption and may reduce its clinical effects (4412,4453,4531,4535,9630).

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ANTIPSYCHOTIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, the risk for manganese toxicity might increase when taken with antipsychotic drugs.  Details Hallucinations and behavioral changes have been reported in a patient with liver disease who was taking haloperidol and manganese. Researchers speculate that taking manganese along with haloperidol, phenothiazine-derivatives, or other antipsychotic medications might increase the risk of manganese toxicity in some patients (61493).

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, manganese might reduce the absorption of quinolone antibiotics.  Details Manganese is a multivalent cation. Interactions resulting in reduced quinolone absorption have been reported between quinolones and other multivalent cations, such as calcium and iron (488).

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, manganese might reduce the absorption of tetracycline antibiotics.  Details Manganese is a multivalent cation. Interactions resulting in reduced tetracycline absorption have been reported between tetracyclines and other multivalent cations, such as calcium and iron (488).

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General ...Orally, boron is generally well tolerated when used in doses below the tolerable upper intake level (UL) of 20 mg. Vaginally, boron is well tolerated.
Most Common Adverse Effects:
Orally: Anorexia, dermatitis, erythema, indigestion.
Vaginally: Burning and pain.

Dermatologic ...Orally, chronic use of 1 gram daily of boric acid or 25 grams daily of boric tartrate can cause dermatitis and alopecia (7135).
Larger doses can result in acute poisoning. Symptoms of poisoning in adults and children may include skin erythema, desquamation, and exfoliation (17).

Gastrointestinal ...Orally, chronic use of 1 gram daily of boric acid or 25 grams daily of boric tartrate can cause anorexia and indigestion (7135).
Larger doses can result in acute poisoning. Children who have ingested 5 grams or more of borates can have persistent nausea, vomiting, and diarrhea leading to acute dehydration, shock, and coma. Adults who have ingested 15-20 grams of borate can exhibit nausea, vomiting, diarrhea, epigastric pain, hematemesis, and a blue-green discoloration of feces and vomit (17).

Genitourinary ...Vaginally, boric acid can cause vulvovaginal burning and dyspareunia in males if intercourse occurs shortly after vaginal treatment (15447).

Neurologic/CNS ...Orally, large doses can result in acute poisoning. Poisoning with boron can cause hyperexcitability, irritability, tremors, convulsions, weakness, lethargy, and headaches (17).

Ocular/Otic ...Exposure to boric acid or boron oxide dust has been reported to cause eye irritation (36852).

Pulmonary/Respiratory ...Exposure to boric acid and boron oxide dust has been reported to cause mouth and nasal passage irritation, sore throat, and productive cough (36852).

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General ...Orally, copper is generally well tolerated when consumed in doses below the tolerable upper intake level (UL).

Dermatologic ...Contact dermatitis caused by copper has been reported rarely. A case report describes a 5-year-old male who developed recurrent fingertip dermatitis and a positive skin test to copper after playing with toy cars made with a copper-containing alloy (95538). Also, in a small clinical trial in children 1-3 months of age with umbilical granuloma, 3 of 33 children receiving a single topical application of copper sulfate developed superficial burns, whereas no superficial burns occurred in those receiving topical sodium chloride (109403).
In one case report, a 68-year-old male with type 2 diabetes and peripheral neuropathy developed second- and third-degree burns after wearing a copper-containing compression sock on the right leg for 3 hours while sitting in the sun. The patient received treatment with topical silver sulfadiazine and oral clindamycin. After 6 weeks, the patient was found to have multiple persistent wounds containing necrotic tissue which required debridement, daily dressing changes, and tubular compression. It is thought that the heat conductance of copper magnified the effects of sun exposure in this case (109402).

Endocrine ...There is evidence from observational studies that people with diabetes (type 1 or type 2) have higher copper levels in their blood than people without diabetes, although not all studies have shown this (95537). It is not known if elevated copper levels contribute to development or worsening of diabetes.

Hematologic ...A case report of copper overdose in a 28-year-old male resulted in hemolysis exacerbated by glucose-6-phosphate dehydrogenase deficiency. The patient was hospitalized, received D-penicillamine chelation, blood transfusion, and ultimately, 4 cycles of plasmapheresis which led to clinical recovery (112378).

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General ...Orally and parenterally, manganese is generally well tolerated when used in appropriate doses. High doses might be unsafe.
Serious Adverse Effects (Rare):
All routes of administration: Neurotoxicity, including Parkinson-like extrapyramidal symptoms, when used in high doses.

Cardiovascular ...Chronic occupational exposure to manganese dust or fumes can cause orthostatic hypotension, and heart rate and rhythm disturbances (61363).

Endocrine ...Chronic occupational exposure to manganese dust or fumes can cause elevations in thyrotropin-releasing hormone (TRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels (61378).

Hepatic ...Manganese intoxication may cause cirrhosis and hepatic steatosis. In one case, a 13-year-old female with manganese intoxication developed severe, life-threatening neurological symptoms, with liver biopsy indicating incomplete cirrhosis and microvesicular steatosis. Chelation therapy and multiple rounds of therapeutic plasma exchange were required before symptoms resolved. The source of manganese exposure was not identified, and it is not clear if the impaired liver function contributed to the manganese accumulation or if elevated manganese exposure led to the liver damage.

Musculoskeletal ...Chronic occupational exposure to manganese dust or fumes has been associated with lower bone quality in females, but not males, suggesting that prolonged manganese exposure might increase the risk of osteoporosis in females (102516). A meta-analysis of 11 observational studies in adults also suggests that increased environmental exposure to airborne manganese sources is associated with lower motor function scores (108537).

Neurologic/CNS ...Orally, there is concern that higher doses of manganese might increase the risk of neurotoxicity, including Parkinson-like extrapyramidal symptoms (7135,10665,10666). One severe case of irreversible Parkinson disease possibly related to taking manganese 100 mg daily for 2-4 years has been reported (96418). In another case, a 13-year-old female with manganese intoxication (diagnosed from blood manganese levels and cranial MRI evidence) developed severe neurological symptoms including loss of consciousness, decorticate posture, clonus, increased reflexes in the extremities, isochoric pupils, and no painful stimulus response. Liver biopsy also showed incomplete cirrhosis and microvesicular steatosis. The patient was intubated, and chelation therapy and multiple rounds of therapeutic plasma exchange were required before symptoms resolved. The source of the child's manganese exposure was not identified (112137). Individuals with impaired manganese excretion can also experience these effects even with very low manganese intake. Manganese accumulation due to chronic liver disease seems to cause Parkinson-like extrapyramidal symptoms, encephalopathy, and psychosis (1992,7135). One review recommends stopping supplementation if aminotransferase or alkaline phosphatase levels rise beyond twice normal (99302).
Chronic occupational exposure to manganese dust or fumes can also cause extrapyramidal reactions (1990,7135). In 1837, Couper observed that exposure to manganese dust particles produces a neurological syndrome characterized by muscle weakness, tremor, bent posture, whispered speech, and excess salivation (61264). Additionally, observational research in children has found that elevated manganese levels detected in the hair and fingernails due to environmental exposure may be associated with impaired neurocognitive function or development (108535). A meta-analysis of 11 observational studies in adults also suggests that increased environmental exposure to airborne manganese sources is associated with lower cognitive function scores (108537).
Intravenously, manganese might increase the risk of neurotoxicity when administered at high doses or for an extended duration. Cases of Parkinson-like symptoms have been reported in patients receiving parenteral nutrition containing more than 60 mcg of manganese daily. Moderate MRI intensity uptake for manganese in the globus pallidus and basal ganglion areas of the brain has been shown in patients receiving parenteral manganese (96416,99302).

Psychiatric ...Chronic occupational exposure to manganese dust or fumes can cause mood disturbance and dementia (1990,7135). A case report describes a man who presented with confusion, psychosis, dystonic limb movements, and cognitive impairment after chronic industrial manganese exposure (99415). Symptoms of manganese toxicity from inhalational exposure develop slowly with initial fatigue and personality changes, progressing to hallucinations, delusions, hyperexcitability, Parkinson-like symptoms, dystonia, and dementia (99415). Additionally, observational research has found that chronic environmental exposure to manganese sources such as mining operations and various industrial processes may be associated with a greater risk for developing symptoms of depression (108536).

Pulmonary/Respiratory ...Chronic occupational exposure to manganese dust or fumes can cause acute chemical pneumonitis, pulmonary edema, or acute tracheobronchitis (61495).

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