C H A P T E R

37

Germanium*
LARRY S. KEITH, OBAID M. FAROON, NIKKI MAPLES-REYNOLDS, AND BRUCE A. FOWLER

ABSTRACT dioxide (GeO2), but may not directly damage DNA;

however, more research is needed. There is little infor-
Animal experimental data show that germanium mation on the toxicity of inorganic germanium com-
compounds, both inorganic and organic, are rapidly pounds to humans, except that germanium tetrachloride
and almost completely absorbed from the lungs and may produce skin irritation and germanium health sup-
the gastrointestinal tract. The distribution among the plements have been linked to serious health effects in
organs and tissues is fairly uniform, but there is evi- humans. In clinical trials, spirogermanium, an organo-
dence of an initial preference for kidney and liver, germanium antitumor agent, has been shown to be neu-
followed by rapid urinary excretion and long-term rotoxic. For these and other reasons, the U.S. Food and
accumulation in the bone. Data on biological half- Drug Administration (FDA) authorized the detention
times are inadequate, but for the rat the whole-body of germanium products labeled to claim human health
retention half-time is estimated to be approximately benefits. In addition, the American Cancer Society con-
1.5 days. siders that germanium supplements may be harmful
Germanium tetrachloride is a strong irritant of and that delaying conventional medical care to take ger-
the respiratory system, skin, and the eye, possibly manium compounds could seriously impact health.
because it is easily hydrolyzed, producing hydrogen High doses of germanium compounds (taken as sup-
chloride; in mice, high-level inhalation exposures plements) induced remarkable lactic acidosis, hydropic
cause necrosis of the tracheal mucosa, bronchitis, degeneration of the proximal convoluted tubules with
and interstitial pneumonia. Systemic toxicity of ger- presence of inclusion bodies, and some cellular necro-
manium compounds is comparatively uncommon; sis and subsequent renal failure; however, the renal
however, when overexposure occurs, nephropathy, glomeruli and the renal interstitial tissue seemed nor-
neuropathy, and hepatotoxicity are usually observed. mal. Neurological effects involved negative deep ten-
Trialkylgermanium compounds are less toxic than don reflexes in the lower extremities and a persistent
the corresponding lead or tin alkyls, and current evi- tingling sensation of the palms and soles. In addition to
dence suggests that germanium is not carcinogenic. severe cardiac dilation, vacuolar degeneration of myo-
Dimethylgermanium oxide is teratogenic in chickens, cardial cells and interstitial edema were observed.
but sodium germanate has not produced malforma- Inhalation is the main route of occupational exposure
tions in hamsters. to germanium during its production and that of related
Cell culture studies show that water-soluble nanopar- products; the main source of exposure for the general
ticle germanium may be more toxic than germanium population is germanium naturally present in food.
Short reviews on the toxicology of germanium and
* The findings and conclusions in this chapter are those of the
its compounds have been published by Mogilevskaja
authors and do not necessarily represent the views of the Agency for (1973), Underwood (1977), Aldridge (1978), Ohri et al.
Toxic Substances and Disease Registry. (1993), and Tao and Bolger (1997).

Handbook on the Toxicology of Metals 4E Copyright © 2015 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/B978-0-444-59453-2.00037-8 799 Portions of the chapter are in the public domain
800 Larry S. Keith, Obaid M. Faroon, Nikki Maples-Reynolds, and Bruce A. Fowler

1  PHYSICAL AND CHEMICAL PROPERTIES 2  METHODS AND PROBLEMS OF

ANALYSIS
Germanium (Ge): atomic weight, 72.63
­(ChemIDplus, 2013) or 72.64 (NIST, 2013); atomic Inductively coupled plasma mass spectrometry
number, 32; density, 5.32 g/cm3 (25°C); melting point, (ICP-MS), atomic absorption spectroscopy (AAS),
937.4°C; boiling point, 2830°C; in elemental form it emission spectrography, and spectrophotometry with
is a gray-white, brittle solid; oxidation states +2 and phenylfluorone have been widely used for the analy-
+4. Under the Chemical Abstract Service (CAS) reg- sis of germanium in environmental and biological
istry system, germanium belongs to group IVa of the samples. A system involving continuous flow hydride
periodic table, together with carbon, silicon, tin, lead, generation hybridized with laser-induced breakdown
and the non-naturally occurring element, flerovium. spectroscopy (HG-LIBS) can be used for aqueous sam-
Germanium is a metalloid that exhibits both metallic ples. Transmission electron microscopy (TEM) can ana-
and nonmetallic properties. Important properties that lyze strain on the nanometer scale in Ge semiconductor
may be important in germanium chemistry and toxi- materials (Beche et al., 2013). The limit of detection
cology are the first ionization energy, electronegativ- (LOD) of AAS is of the order of 1.5 mg/L and can be
ity, and covalent radius that are, respectively, 1086 kJ/ reduced by approximately 100 times using a graphite
mol, 2.5, and 77 pm for carbon and 760 kJ/mol, 1.8, tube atomizer (Amos and Willis, 1966; ­Johnson et al.,
and 122 pm for germanium. Bond energies of carbon 1973). To reduce losses because of volatility, biological
and germanium for the halogen series do not vary samples should be ashed at low temperature. Interfer-
greatly. Like other group IVA elements, Ge exhibits ence of other elements can be eliminated by carbon tet-
some P-bonding and forms tetrahedral and some chi- rachloride extraction. Samples are treated in the same
ral compounds (Cotton and Wilkinson, 1988). Ge is an way for spectrophotometry with phenylfluorone, for
N- or P-type semiconductor, depending on the impu- which the LOD is approximately 0.1-0.5 mg/L (Luke
rities present. and Campbell, 1956). The achievable precision (relative
The Chemical Abstracts System (CAS) numbers for standard deviation) of the spectrophotometric method
metallic germanium, the isotope 68Ge, and some other is 5-10% (Schroeder and Balassa, 1967a). There is not
germanium compounds addressed in this chapter are enough information presented in these early reports to
shown below. evaluate the accuracy of the analytical methods used.
   Atomic emission spectrometry (AES) of germanium
Germanium metal, 7440-56-4 in environmental samples was described by Braman
68Ge, 15756-77-1 and Tompkins (1978); germanium compounds are
Carboxyethylgermanium sesquioxide, converted in aqueous solution to volatile hydrides by
12758-40-6 reduction with sodium borohydride. The detection
Dimethylgermanium oxide, 5061-27-8 limit of AES was estimated to be approximately 0.004-
Germanium dioxide, 1310-53-8, 0.014 mg/L and the precision to be approximately 3%.
Germanium tetrachloride (also germanium Although the detection limit in aqueous samples for
­chloride), 10038-98-9 HB-LIBS is significantly higher at 0.2 mg/L, sample
Germanium tetrahydride (also germanium processing may be sufficiently fast to enable continuous
­hydride), 7782-65-2 environmental monitoring (Yesiller and Yalcin, 2013).
Germanium sesquioxide, 59087-76-2 The detection limit for spark source mass spectrom-
Sodium germanate, 12529-48-5 etry (SSMS; human tissue) after samples are ashed is
Spirogermanium 41992-23-8 0.007 mg/kg wet weight (Hamilton et al., 1972/1973).
Tetraalkylgermanium (e.g. tetrabutylgerma- Proton activation can also be used for the analysis of
nium, 1067-42-1; tetraethylgermanium, 597-63-7; germanium in biological samples; it has a detection
­tetrapentylgermanium, 3634-47-7). limit of approximately 0.7 mg/kg (Bonardi et al., 1982).
   Diffusion phoresis has been proposed for the analysis
CAS numbers are not available for some other of gas mixtures containing germanium compounds
germanium compounds (e.g. germanium dichloro (Minjajlo et al., 1978). Swennen et al. (2000) have
tetrakis (l-cysteinyl-alpha-tocopherol amide) dichlo- described an air-sampling method that uses a CIP-10
ride, hexaalkyldigermanium oxides, g ­ermanium dust sampler that maintains 10 mL of air/minute flow
biotite, germanium apatite, germanium-­ lactate- through high-speed rotary polyurethane foam filters
citrate, and germanium acetate) (ChemIDplus, on which small Ge particles (inhalable or respirable)
2013). are collected separately. Collectible dust on the filter is
 37 Germanium 801

then measured using AAS with a flame (N2O; C2H2) or Adsorptive stripping voltammetry (AdSV) is based
modified by procedures using AA-10 or FIAS-400. The on the adsorptive accumulation of germanium com-
measurement reliability for this technique was reported plex on bismuth film electrode (Zhong et al., 2013). The
as being down to 10 ng Ge/m. A method for analyzing testing of trace germanium in the presence of pyrogal-
germanium hydride in occupational air over the range lol in Chinese herbal remedies was performed. The
0.85-300 μg/L was developed using cellulose filters ana- LOD was 60 ng/L, with a relative standard deviation
lyzed using atomic fluorescence spectrometry (AFS) of 3.73% at 5 μg/L (n = 9).
that achieved a 0.5 μg/L LOD (Zhang et al., 2011). Relatively inexpensive sodium iodide (NaI)-based
ICP-MS is the preferred technique for the measure- spectrometers have been used to measure radioac-
ment of multiple elements, including Ge, in the same tivity in blood for small animal research. A bismuth
sample. Different applications have been developed germanate (BGO) detector was found to be an effec-
for controlling various parameters, including specia- tive replacement for NaI, and its ability to achieve a
tion, molecular structure, and total concentration. The comparable LOD with less blood may be beneficial
accurate analysis of germanium in medicines was for research where limited blood can be obtained from
evaluated, and the difficulty in accounting for inter- animals (Yamamoto et al., 2012).
ferences caused by various radionuclides (85Rb, 88Sr,
89Y, 90Zr, 93Nb) was overcome by using a higher resolu-

tion mode of HR-ICP-MS than that normally used for 3  PRODUCTION AND USES
analyzing those radionuclides (Krystek and R ­ itsema,
2004). Urinary germanium concentrations can be
3.1 Production
used as a biomarker of inhalation exposure to air-
borne dust from metallic germanium or g ­ ermanium Some zinc and lead-zinc-copper sulfide ores are
dioxide (GeO2) in an occupational setting. A novel readily available sources of germanium, but there is no
approach for analyzing such samples involving a widely occurring germanium ore. The concentration of
hydride generation-based method coupled with flow- germanium in the Earth’s crust ranges between 1.5 and
injection graphite furnace AAS (­HG/FI-GFAAS) has 7 ppm (Scansetti, 1992). The total estimated world pro-
been described (Roels and Buchet, 2001). The LOD for duction of germanium was approximately 114,000 kg
this method was 0.25 μg/L germanium. The determi- in 1982, but this did not include production in Zaire,
nation of germanium in human samples with graph- which had one of the largest resources but for which
ite furnace AAS (GFAAS) and microwave-induced no production data were available. World production
plasma mass spectrometry (MIP-MS) was described was estimated to be 44,000 kg in 2003 and 50,000 kg in
by Shinohara et al. (1999). The LODs were 3 ng/mL 2005 (USGS, 2005); this increased to 128,000 kg in 2012.
for GFAAS and 0.05 ng/mL for MIP-MS. The sensi- U.S. production (stable at 3000 kg/year in 2010-2012)
tivity of GFAAS was found to be lower than that of is expected to increase, with a T
­ ennessee plant starting
MIP-MS (Shinohara et al., 1999). A similar analyti- production of a germanium concentrate and an addi-
cal method was described by Swennen et al. (2000) tional plant being added in New York. GeO2 sold at
to measure Ge urine concentrations in workers after U.S.$925/kg in March 2012 and increased to U.S.$1375/
occupational exposure. Ge levels in urine were mea- kg in ­September 2012 due to supply limitations caused
sured by FI-GFAAS. This method consisted of five by three Chinese plants shutting down to address envi-
consecutive steps: mineralization of urine, pH condi- ronmental issues and Japan having to import germa-
tioning, generation of gaseous GeH4 by flow injection, nium as a result of the Great East Japan earthquake and
GeH4 trapping in an iridium-coated graphite furnace, tsunami in 2011. Approximately 60% of germanium
and ultimate electrothermal atomization of Ge. The metal and 30% of Ge consumed each year is recovered
reported LOD was 0.25 μg Ge/L of urine. from recycled materials. G­ ermanium can also be recov-
Krystek and Ritsema (2004) reported a combined ered from the waste products of coal and coke technol-
HPLC-ICP-MS analytical system for speciating both ogy such as ash and flue dusts (USGS, 2013).
inorganic and organic Ge compounds in commercially The significant need for germanium as a semicon-
available medical compounds used in clinical treat- ductor material has led to advances in germanium
ments for cancer and acquired immunodeficiency product production. Germanium crystals used as radia-
syndrome (AIDS). These analytical methods were con- tion detectors in the 1970s had to be drifted with a thin
firmed by nuclear magnetic resonance (NMR). The total layer of lithium to compensate for crystal impurities,
germanium concentration was found to be 4.6 mg/g which required the detector to be cooled to liquid nitro-
sample by HR-ICP-MS and 5.7 mg/mL by NMR. gen temperatures to preclude further Li diffusion; the
802 Larry S. Keith, Obaid M. Faroon, Nikki Maples-Reynolds, and Bruce A. Fowler

production of high-purity germanium (HpGe) in the germanium tetrahydride (germane), germanium tet-
1980s resolved this, allowing detectors to be tempera- rachloride, and some organogermanium compounds,
ture cycled without harm. Germanium is widely used such as alkylgermanium and hexaalkyldigermanium
in the electronics industry, which is moving toward oxides, and nanoparticle germanium. An example of
smaller and more powerful devices requiring small, an organogermanium compound of historical thera-
high density semiconductor materials. One goal is to peutic interest is spirogermanium, an azaspiran with
produce molecular electronic devices. Ge quantum germanium substituted for one carbon moiety in the
dots of high density with tight particle sizes in the ring structure (Jao et al., 1990; Schein et al., 1980). Ger-
low nanoparticle size range were made by sputtering manium compounds have the potential to be used as
Ge onto a matrix under a noble gas atmosphere using antidotes for reducing the acute toxicity and increasing
a radio frequency magnetron (Samavati et al., 2012). A the urinary excretion of selenium. In rats, 40 mg Ge/kg
demonstration method was developed to form organic subcutaneously has been reported to reduce the sele-
monolayers composed of Si-aryl and Ge-aryl combina- nate-induced body weight loss, and pretreatment with
tions and directly bonding them to a semiconductor sur- germanium sesquioxide enhanced urinary excretion of
face (Yamanoi et al., 2012). Monolayer passivation of Ge 75Se in a dose-related manner (Paul et al., 1989).

molecular wires designed to improve lithium-ion bat- 18F-fluorodeoxyglucose (FDG) is the standard medi-

tery performance was demonstrated (Yuan et al., 2012). cal injectable for positron emission tomography (PET)
imaging. The peptide, 68Ga-1,4,7,10-tetraazacyclodec-
ane-1,4,7,10-tetraacetic acid (68Ga-DOTA), using 68Ga
3.2 Uses
eluted from a 68Ge generator, has been developed as an
The largest end use of germanium is now in the alternative to FDG for PET imaging purposes, particu-
production of infrared sensing and identification sys- larly for neuroendocrine and neuroectodermal tumors,
tems. Its use in fiber optical systems has also increased, that may be useful for facilities that do not have local
whereas the consumption for semiconductors has con- cyclotron production capabilities (Pagou et al., 2009).
tinued to decline because of advances in silicon semi- Germanium detectors are used in various industrial
conductor technology. The estimates of the end uses for and clinical settings. Lithium-drifted germanium semi-
germanium worldwide are as follows: fiber optic sys- conductor (GeLi) detectors for measuring radioactivity
tems, 30%; polymerization catalysts, 25%; e­ lectronics/ in gamma-emitting radionuclides require cooling with
solar electrical applications, 15%; and other (phos- liquid nitrogen; such detectors were introduced in the
phors, metallurgy, and chemotherapy), 5%. For the 1970s. They have now been largely replaced with high-
United States, the estimates are somewhat different: purity intrinsic germanium (HpGe) detectors that allow
infrared optics, 50%; fiber optic systems, 30%; infrared temperature cycling. These detectors are used in situ to
optics, 30%; electronics/solar electrical applications, measure the radioactivity of biological and environ-
15%; and other (phosphors, metallurgy, and chemo- mental media, as well as the quantity and distribution
therapy), 5%. The primary difference is the absence of radioactive material inside humans. Although the
in use of germanium as a polymerization catalyst in detection efficiency is less than that for thallium-acti-
the United States (USGS, 2013). Other applications vated sodium iodide detectors of the same volume, the
include production of phosphors, correction inhibition energy resolution is greatly superior, allowing a peak
in alloys, glass of high refractive index, and spiroger- resolution of a few kiloelectron volts (keV). Germanium
manium for cancer therapy (no longer for approved detectors are also used to image X-rays and measure the
use) (Scansetti, 1992). Germanium tetrachloride is an bone mineral content, particularly of vertebrae, after
intermediate in the preparation of germanium dioxide adjusting for lean and adipose tissue thickness (Jonson
and organogermanium compounds. Several germa- et al., 1986). A HpGe detector has been used as a com-
nium compounds have potential uses in pharmacol- ponent monitoring system for routine assessments of
ogy, pharmacy, cosmetics (Kenney, 1980; Ohara, 1977; 125I uptake in the thyroid gland of radiation workers.

Tomizawa et al., 1978; Lim et al., 2010), and cancer Using a whole-body counter with a protective shield-
chemotherapy (Budman et al., 1981; Kakimoto and ing chamber, a minimum detectable activity of 2.2 Bq
Miyao, 1979; Kumano et al., 1978; Schein et al., 1980). was obtained. The system could measure an activity of
Nanotechnology research has discovered a promising 128 Bq with an uncertainty of ±5% (Kopp et al., 1994).
new use of Ge as nanowires for optoelectronic devices Bismuth germanate (BGO) radiation detectors
(field effect transistors, photoresistors, lithium-ion are typically used in producing PET medical X-ray
batteries, and fluid sensors) (Pei and Cai, 2012). Of images for locating human cancer foci. A PET sys-
industrial and toxicological interest are elemental tem has good but limited spatial resolution to locate
germanium, germanium dioxide, sodium germanate, small tumors and identify inhomogeneities in glucose
 37 Germanium 803

metabolism that help in determining whether a tis- and additives can alter elemental content, can sig-
sue is cancerous. Such resolution is a function of the nificantly change these intake estimates (e.g. the Ge
type of detector used. Shiga et al. (2009) evaluated a content was 0.1 μg/g for Barbados brown sugar and
conventional BGO imaging system against one using 0.03 μg/g for Demerara sugar) (Hamilton and ­Minski,
cadmium telluride (CdTe) semiconductor detectors in 1972/1973). A 1994 total diet study in the United
10 patients with nasopharyngeal cancer and in 6-mm Kingd­ om found the germanium concentration to
and 25-mm cold spot phantoms. Compared to the BGO range from < 2 to 4 μg Ge/kg fresh food weight, with
system, the CdTe system (modified to avoid potential the highest levels found in cereals (4 μg/kg) and bread
loss of energy resolution) was found to have compa- (3 μg/kg) (FSA, 1997). A spectrophotometric method
rable energy resolution (4.1% full width at half maxi- that used phenylfluorone showed the presence of
mum), better spatial resolution, and lower noise (i.e. germanium in all food items analyzed ­
­ (Schroeder
less Compton scattering). This provided an improved and ­ Balassa, 1967a). However, only five items had
ability to identify tumor edge nonuniformity and the more than 2 mg Ge/kg (raw clams, canned tuna, dried
extent of tumor inhomogeneity (Shiga et al., 2009). pan fish, canned baked beans, and tomato juice), and
Osman et al. (2003) studied medical scans from 300 15 items contained more than 1 mg Ge/kg.
patients and determined that image standardization A more recent UK dietary exposure assessment
attenuation correction of a PET image or PET/computed for Ge and 23 other substances was conducted as the
tomography (CT) fusion using a CT scan produced errors 2006 UK Total Diet Study. Of the 20 food groups tested
in 6% of lesion localizations, some considered serious. in 24 UK towns, Ge was detected in only two (meat
For example, actual liver dome lesions were incorrectly products at 1 μg/kg and offal at 2 μg/kg). Estimated
determined to be in the lower right lung. Such errors dietary exposure decreased from 4 μg/day in 1994 to
were found not to occur when germanium was used for 0.1-1.5 μg/day in 2006. No explanation was offered
attenuation correction of PET scans (Osman et al., 2003). for the decrease, but the conclusion was that the esti-
Results from the transmission scanning of 68Ge rods was mated dietary intake of Ge in adults is not of health
used to improve the accuracy of the photon attenua- concern (Rose et al., 2010).
tion factor used to correct PET emission data for cancer A French total diet study from 2006 to 2007 evalu-
therapy patients undergoing hybrid PET/CT modality ated 40 intake categories of food and liquid by age and
scanning, thus improving the accuracy of images used gender. The highest levels of Ge were found in butter,
in evaluating the efficacy of their treatment (Burger et al., offal, chocolate, and delicatessen meats (∼5-9 μg/kg)
2002). However, attenuation correction with 68Ge may with undetectable levels in 83% of samples (LOD
not be sufficient to remove artifacts when areas near hip ∼4 μg/kg). The mean lower bound and mean upper
prosthetic materials are imaged; in such cases, atten- bound intake ranges (in μg/kg/day) reported were
uation-weighted iterative reconstruction can improve 0.0838-0.1791 (children aged 3-6 years), 0.0651-0.1350
image quality (Goerres et al., 2003). (children aged 7-10 years), 0.0460-0.0942 (children aged
A planar hyperpure germanium detection system 11-14 years), 0.0352-0.0733 (children aged 15-17 years),
was used to show that X-ray scattering profiles can 0.0446-0.0914 (women of childbearing age 18-45 years),
be used to differentiate among normal, fibrotic, and and 0.0392-0.0841 (women aged 65 and older). Values
malignant cells in samples of human breast tissue. for men were not reported (ANSES, 2011).
Scatter patterns measured with the detector at a fixed Selected hospital diets contained on average 0.88 mg
scattering angle of 6° from the incident beam were suf- Ge/kg wet weight. The daily intake of germanium may
ficiently different to enable samples containing malig- vary from 0.4 to 3.5 mg (Schroeder and Balassa, 1967a).
nant cells to be identified. However, the type of cancer Hamilton and Minski (1972/1973) estimated the mean
could not be resolved (Changizi et al., 2008). daily intake in the United Kingdom to be 0.367 ± 0.159 mg
by SSMS. The estimated dietary intake for a “reference
man” is approximately 1.5 mg Ge/day, of which 96% or
more is absorbed (Snyder et al., 1975). The mean human
4  ENVIRONMENTAL LEVELS AND
daily intake of Ge from food is estimated to be 1.5 mg
EXPOSURES
(with a range of 0.40-3.40) (Schauss, 1991b).
4.1  Food and Daily Intake
4.1.1  Water, Soil, and Ambient Air
A total diet study in the United Kingdom for 1966-
1967 reported that the total daily intake estimated for Braman and Tompkins (1978) used AES to measure
Ge was 367 ± 159 μg/day. The authors pointed out that Ge concentrations in U.S. freshwater and saline sam-
­consuming processed foods, for which the processes ples. They reported a concentration range from < 4 to
804 Larry S. Keith, Obaid M. Faroon, Nikki Maples-Reynolds, and Bruce A. Fowler

600 ng/L (Oregon well waters); in some saline waters, to ­ germanium concentrations up to approximately
the concentration range was from < 4 ng/L to approxi- 7 mg/m3) have been reported to occur in the produc-
mately 200 ng/L. Reimann et al. (1996) analyzed 145 tion of germanium monocrystals. In some cases, the
hard rock groundwater and surface water samples from samples contained up to 30% free silica (Goldman, 1960;
Norway and Finland and found the median content of ­Mogilevskaja, 1973). Swennen and coworkers observed,
germanium to range between 0.015 and 0.44 μg/L. for exposed and control workers, no significant differences
Samples of soils in the United States contained in the germanium urine levels taken at the beginning and
0.6-1.3 mg Ge/kg (Schroeder and Balassa, 1967a), the end of the workweek. These authors also reported no
which is of the same order of magnitude as the abun- overt clinical health effects for the two groups of workers;
dance of germanium found in the Earth’s crust (1.5 mg/ however, slightly higher than control levels of albumin
kg) (Fyfe, 1974). and transferrin and some low molecular weight proteins
Considerable amounts of Ge are discharged into the were reported in exposed workers, as discussed later. The
atmosphere by coal combustion. Paone (1970) estimated geometric mean of the cumulative frequency of germa-
2000 tons per year to be discharged in stack gases, flue nium levels in the air during five working days ranged
dusts, and ashes from coal-burning plants in the United from 1.07 to 5.11 μg/m3 (Swennen et al., 2000). ­Hamilton
Kingdom. Coal ash may contain 20-280 mg Ge/kg (Coal et al. (1972) e­valuated the importance of cleanliness
Research Section, 1972). Concentrations of germanium in between sample collection and analysis and found that
air particulates may range from < 0.01 ng/m3 to approxi- the respective concentrations of germanium in laboratory
mately 1700 ng/m3 (Braman and Tompkins, 1978). and ambient air were < 2 × 10−2 and 19.7 ± 7.0 μg/g dust.
Ge is a primary pollutant in the leather industry
(Zhang and Zhang, 2007). The river water concen-
tration in one Chinese watershed increased 14-fold 5 TOXICOKINETICS
between 1992 and 1998 and correlated well with
leather industry discharges. Such a correlation was not 5.1 Absorption
realized in another watershed, perhaps indicating that
5.1.1 Inhalation
primary Ge releases to that watershed were from other
industries, e.g. semiconductor. Dudley (1953) reported the rate of clearance of depos-
ited elemental germanium particles (mean size 1.4 μm)
4.1.2  Plants, Fishery Products, and Microbial from the lungs of rats to be exponential (52% in 24 h,
Organisms 18% remaining 7 days after exposure). Radiochemical
examination of the tissues showed that part of the mate-
Germanium is a constituent of various medici- rial entered the circulation and reappeared in the kidney
nal plants and microorganisms (Park and Han, 1979; and liver 1 h after exposure. The clearance of germanium
Slawson et al., 1992; Staufer, 1980). Germanium has
­ dioxide particles (mean size 0.4 μm) was more rapid than
been found to accumulate in a variety of microorgan- that of elemental Ge particles (79% within 24 h).
isms, with the accumulation rate depending on environ-
mental pH, temperature, and silicic acid concentration 5.1.2 Ingestion
within the cell. Growth inhibition by GeO2 was more
observed and pronounced in yeast than in bacteria (Lee Neutralized Ge dioxide was rapidly absorbed in rats
et al., 1990). Traces of Ge usually exist in soil, plants, and after gavage (73.4% in 4 h, 96.4% in 8 h) (Rosenfeld, 1954).
animal tissues; however, high concentrations (2-9 ppm) Equally rapid absorption of tetraethylgermanium from
of Ge may be found in beans, tomato juice, oysters, tuna, the gastrointestinal tract of mice was found by Caujolle
garlic, aloe vera, ginseng, shelf fungus, and green tea. et al. (1963). Schroeder and Balassa (1967a) reported that
Tissue levels higher than 5 ppm are toxic to most plants. the concentrations of germanium ­eliminated in human
Hamilton and Minski (1972) reported germanium levels urine were approximately the same as concentrations
in animal DNA (salmon sperm, 0.7 ppm; herring sperm, in the diet, and concluded that dietary germanium was
5.3 ppm; and calf thymus, 2.7-2.9 ppm) and in microor- well absorbed. Ge was almost completely absorbed
ganism RNA (yeast, 0.3 and 3.3 ppm). after oral exposure and was excreted from the human
body within 3 days (Ohri et al., 1993).

4.2  Working Environment 5.1.3 Dermal

Exposure to Ge tetrachloride and its hydrolysis The dermal absorption of GeO2 in male F344/N rats
products (GeO2 and HCl) may occur in production was studied by applying 0, 0.14, and 0.29 mg Ge/g as
­processes for germanium and its compounds. Dust con- GeO2 in hydrophilic ointment to unabraded shaved
centrations ranging from 5 to 70 mg/m3 (corresponding and depilated skin via occlusion dressing for 72 h.
 37 Germanium 805

Organ levels increased with dose and elevated levels that the radiolabeling of germanium chloride was
were found in plasma, liver, and kidney, indicating that incomplete or that the radionuclide was in a some-
GeO2 is absorbed through the skin (Yokoi et al., 2008). what different form which bound differently to organ
proteins. Much of the injected germanium had been
excreted by 7 days; most of the remaining portion was
5.2 Distribution
bound to the larger molecular components, helping to
Shamberger et al. (2003) measured germanium in explain its longer term retention.
blood and reported that the concentration was statis- Schroeder and Balassa (1967b) and Schroeder
tically significantly elevated (p <  0.05) in women with et al. (1968) kept mice and rats for life on a normal
premenstrual syndrome (0.503 ±  0.532 ppm) compared laboratory diet (0.33 mg Ge/kg) and drinking water
with that for asymptomatic women (0.29 ±  0.22 ppm). containing 5 mg Ge/L as sodium germanate. Germa-
The authors noted that these groups have significantly nium was widely distributed in the body, and there
different dietary habits, with the former having food was no selective retention or storage. Essentially the
cravings and less nutritious diets, and thus differ- same distribution was found in mice after inges-
ent germanium intakes. Since osteoporosis may be a tion of tetraethylgermanium (Caujolle et al., 1963).
concern in both premenstrual and postmenopausal Nagata et al. (1985) did a case study of a patient who
women, Qin et al. (2013) studied the potential for using took 600 mg/day of a germanium-containing elixir
germanium in postmenopausal osteoporosis therapy and subsequently died of kidney failure, germanium
in ovariectomized rats. Although oral germanium was found to be present at elevated levels in almost
decreased urine calcium content, it did not decrease every organ compared with a nonconsumer who
calcium solubility that germanium exposure might not died of liver cirrhosis. The respective organ concen-
help resolve osteoporosis. trations in μg/gm wet tissue for Ge patient/(non-
In rats, absorbed Ge was found to be fairly uni- consumer) were spleen, 19.804/(0.108); vertebra,
formly distributed between erythrocytes and plasma 16.926/(8.820); renal cortex, 3.184/(0.046); brain,
(2:3) and not bound to plasma proteins (Rosenfeld, 3.108/(0.189); and skeletal muscle, 2.758/(0.030). In
1954). In exposed rabbits and dogs [intravenous addition, Morita et al. (1986) and Asaka et al., (1995)
(i.v.) injection of GeO2], the highest concentrations reported high accumulation of germanium in the
were identified in the kidney, liver, spleen, gastroin- hair (56.4-173.7 μg/g), fingernails (5.4-35 μg/g), and
testinal tract, and bone (Dudley and Wallace, 1952). toenails (14-15.8 μg/g) of three individuals who con-
Sabbioni et al. (2010) studied Ge distribution in nine sumed a germanium-containing nutritional supple-
male Sprague-­ Dawley rats injected intraperitone- ment for 1-1.5 years.
ally (i.p.) with 20 ng of Ge (80 ngGe/kg) as radioac- The distribution and residence time of Ge was
tive 68GeCl4. At 24 h, the Ge tissue concentration in studied in rats after a tail vein injection of radio-
decreasing order was the kidney (0.22 ng Ge/g, 1.08% active 68GeCl4 followed by serial sacrifice. Ge was
of the dose), liver, large intestine, femur, muscle, tes- present in all 17 rat organs evaluated, and its resi-
tes, and blood (0.0007 ng Ge/mL, 0.003% of the dose), dence time in organs decreased in the order of
for which germanium in the latter was distributed kidney, liver, bone, muscle, and bone marrow
equally between plasma and red blood cells. By day (Velikyan et al., 2013).
7, levels dropped tenfold and sixfold in the kidney The potential for Ge to be metabolized in vivo was
and liver, respectively, but by only 30% in the femur, studied by injecting GeO2, tellurite, and antimonite
indicating that bone could be a long-term repository. into rats and analyzing potential metabolites. Ge was
Intracellular hepatic distribution was mainly to the not found to undergo methylation (Kobayashi and
cytosol, followed by the nucleus, microsomes, mito- Ogra, 2009).
chondria, and lysosomes. This differed markedly
from renal distribution, for which distribution (com-
5.3 Excretion
pared with liver) was much higher in the cytosol (59%
vs. 38%) and much lower in the nuclear fraction (22% Absorbed germanium is preferentially excreted
vs. 31%). The fraction of the germanium dose in mito- in the urine in both humans (Schroeder and Balassa,
chondria was higher in the liver than in the kidney, 1967a) and animals. In rats, 64.8% of an i.p. dose of
indicating that doses high enough to harm the kid- sodium germanate (100 mg/kg) was excreted in urine
ney could also damage the liver. Two days after i.p. and 4.7% in feces within 1 day, with the total excretion
injection, most of the germanium mass was bound to in 5 days amounting to 78.8% and 13%, respectively
low molecular weight components, while most radio- (Rosenfeld, 1954). Excretion from Sprague-Daw-
activity was bound to high molecular weight mol- ley rats injected i.p. with 20 ng Ge (80 ngGe/kg) as
ecules. This apparent inconsistency might indicate 68GeCl was primarily in the urine (14%) and less via
4
806 Larry S. Keith, Obaid M. Faroon, Nikki Maples-Reynolds, and Bruce A. Fowler

feces (0.4%) through day 2, but both normalized to 6  LEVELS IN TISSUES AND BIOLOGICAL
approximately the same rate after that point (­ Sabbioni FLUIDS: BIOLOGICAL MONITORING
et al., 2010). Excretion of germanium by rabbits in
urine after an i.v. injection of GeO2 (13.5 mg in terms Hamilton et al. (1972/1973) published the following
of Ge) amounted within 72 h to 60-77% of the dose; values of germanium content in some “normal” human
6-12% was excreted in the feces (Dudley and Wallace, tissues in the United Kingdom (mean concentration
1952). In dogs, 90% of an injected GeO2 dose (3.4 mg/ in μg/kg wet weight using SSMS): lymph node, 0.009;
kg in terms of Ge) was excreted in the urine within muscle, 0.03; liver, 0.04; lung, 0.09; brain, 0.1; blood, 0.2;
72 h (Dudley and Wallace, 1952). Roels and Buchet testes, 0.5; and kidney, 9.0. The concentrations of ger-
(2001) collected urine samples at the beginning and manium in human lung tissue (SSMS, 247 samples), as
the end of the day shift from workers occupation- reported by Brown and Taylor (1975), ranged from 0.08
ally exposed to Ge or GeO2 by inhalation. Urinary to 12 mg/kg dry weight. Schroeder and Balassa (1967a)
elimination kinetics was studied in seven workers, found 0.29 mg/L in serum, 0.65 mg/L in erythrocytes,
and the urinary elimination rates (half-times) ranged and 1.26 mg/L in urine (spectrophotometry with phenyl-
from 8.2 to 18.1 h. Therefore, germanium urinary fluorone). In one patient who ingested a total dose of 30 g
excretion may be used for biomonitoring of occupa- Ge oxide in capsules over a period of 8 months, Ge con-
tional Ge exposures. Trace levels of Ge in the scalp centrations in μg/gm of wet tissue at autopsy were 2.51
hair of 80 male hemodialysis patients were found to in the renal cortex, 17.70 in the renal medulla, 4.73 in the
be lower than in a healthy male control population myocardium, 20 in the spleen, 1.99 in the cerebrum, and
(Ochi et al., 2011). 8.67 in lymph nodes ­(Matsusaka et al., 1988). ­Swennen
et al. (2000) reported that urinary Ge concentrations
could be used for the biological monitoring of occupa-
5.4  Biological Half-Time
tional Ge exposure (but results indicated that monitoring
By the use of a simple exponential model and should be conducted within a week of exposure to be
­osenfeld’s data (1954) for rats, the biological
R useful). They reported urinary concentrations of < 0.25 μg
half-times can be roughly estimated at 1.5 days for Ge/g creatinine in control workers. In exposed work-
whole-body retention, 2 days for the liver, and 4.5 ers, they reported geometric mean urinary concentration
days for the kidney. The biological half-lives in male (μg Ge/g creatinine) ranges from 1.36 (Monday) to
ICR mouse tissues after GeO2 ingestion and mea- 3.16 (Friday) before the working shift to 4.22 ­(Monday)
surements taken over 24 h were reported as approxi- to 4.34 (Friday) after the working shift. Ranges of
mately 6.3 h in the brain, 3.6 h in the heart and testis, individual values before the shift were 0.23-70  μg/g
2.5 h in the kidney and liver, and 1.2 h in the blood. creatinine and after the shift were 0.16-195 μg/g creati-
The integrated ­germanium doses for those tissues nine. The urinary Ge levels after the shift correlated fairly
(in μg-h/g) were calculated to be 1.5 for the brain, well with the external exposure (ambient concentration
6.5 for the heart and testis, 23 for the liver, and 51 for of inhalable Ge particles) as well as with the airborne
the kidney (Shinogi et al., 1989). In a single oral dose levels of respirable Ge particles. Germanium in non-­
study of GeO2 (100 mg/kg) in male Wistar rats, the occupationally exposed women with premenstrual
maximal mean serum concentration was achieved in syndrome was found to be elevated in red blood cells
0.7 h and an excretion half-time of 2.3 h was observed (0.5 ppm vs. 0.3 ppm in age-matched controls), but not in
(Lin et al., 1999). They also conducted a multi- scalp hair (Shamberger, 2003).
ple dose study for 4 weeks and found the highest
concentrations of Ge in the peripheral nerves and
kidneys. Recently, Velikyan et al. (2013) reported
7  EFFECTS AND DOSE-RESPONSE
that i.v. injected 68Ge was eliminated rapidly, with
RELATIONSHIPS
an initial biological half-time of approximately 0.6 h
in the rat. The authors presumed that such a short 7.1  Inorganic Compounds
half-time was due to renal excretion; however, that 7.1.1  Local Effects and Dose-Response Relationships
value is much smaller than excretion rates reported
in other similar studies addressed in Section 5.3. 7.1.1.1 Animals
Such a value may be more consistent with the effec- Rats showed thickening of the alveolar walls and
tive half-life (accounting for biological plus radio- hyperplasia of pulmonary lymphatic vessels 7 months
logical elimination) of g ­ allium-68, the radioactive after the endotracheal administration of 30, 50, and
progeny of 68Ge, which has a radioactive half-life 70 mg GeO2 (Mogilevskaja, 1973). Changes in the respi-
of 68 min. ratory system after single (1.4-20 g/m3, 2 h) and repeated
 37 Germanium 807

(0.5-0.7 g/m3, 2 h/day, 5 days/week, 8 weeks) inhala- GeO2 for mice ranged from 2025 mg/kg (females, i.p.)
tion exposures of mice to germanium tetrachloride were to 6300 mg/kg (males, orally). The corresponding val-
dose-related and ranged from irritation of the respiratory ues for rats were 1620 mg/kg and 3700 mg/kg. Toxic
system to necrosis of the tracheal epithelium, catarrhal signs included reduced spontaneous activity, sedation,
desquamative bronchitis, and interstitial pneumonia hypothermia, vasodilation, ptosis, cyanosis, and tremor.
(Kal’sada, 1964). No changes in the respiratory system Death was caused by respiratory paralysis (­Hatano
were reported after long-term inhalation exposure of rats et al., 1981a). Eight weekly i.p. doses of neutralized
(3, 4, 5, and 7 mg/m3, duration 4 h/day, 5 days/week, GeO2 (100 mg/kg) did not inhibit the growth of rats,
for 7 months) to germanium tetrachloride (Kurljandskij but ingestion of the same compound in food (1000 mg/
et al., 1968). No local respiratory effects were reported in kg) or drinking water (100 mg/L) inhibited the growth
rats, mice, and guinea pigs after the inhalation of germa- of young rats and caused 50% mortality in 4 weeks.
nium tetrahydride either in acute or chronic experiments After this period, the survivors seemed to recover
(Gus’kova, 1974). On the other hand, oral treatment with even though they continued to ingest approximately
the health supplement carboxyethylgermanium ses- the same dose for another 8 weeks (Rosenfeld and
quioxide (germanium-132 or Ge-132) showed an inhi- Wallace, 1953). GeO2 in doses > 150 mg/kg/day, subcu-
bition of viral growth in the mouse lung. It provided a taneously, for > 30 days inhibited body weight gain and
significant protective effect against a dose of 10 times the motor activity and reduced erythrocytes, hemoglobin
median lethal dose (LD50) of an influenza virus aerosol concentration in blood, and uric acid concentration in
challenge to the mouse. It increased survival rate, pro- urine. Heart hypertrophy, intestinal hemorrhage, and
longed survival time, and prevented the development of lung congestion occurred in some rats. Intraperitoneal
lung consolidation; 20 mg/kg/day for 6 days was found administration of a Ge-132 health supplement to rats
to be the most effective dose protocol (Aso et al., 1989). under urethane anesthesia induced a dose-related drop-
The Yokoi et al. (2008) article addressed in Section 5.1.3 off in the means of arterial blood pressure and heart
found that neutralized GeO2 was absorbed through the rate. The effects of Ge-132 on blood pressure and heart
skin. The authors speculated that rats and humans might rate were probably induced through stimulation of the
be sensitive to this substance and that repeated dermal parasympathetic efferent and inhibition of sympathetic
exposure might pose a potential health hazard. However, efferent central nervous system (Ho et al., 1990). Germa-
the authors did not report any adverse effects in the ani- nium fed to rats as carboxyethylgermanium was found
mals they had studied, and the Rosenfeld (1954) article to reduce the free radical and lipid peroxidase content
they cited already had found that neutralized Ge dioxide in the liver and kidney while increasing glutathione
(topical application, twice a day for 2 weeks) induced no peroxidase (GPx) in the blood, indicating a protective
irritation of the shaved skin of the rat. effect (Xie et al., 1996). Hatano et al. (1981a) observed no
Ulceration and necrosis of the skin were observed specific pathological changes in a 90-day study in rats
in rabbits after 2 h of exposure to germanium tetra- (3-50 mg/kg/day, subcutaneously).
chloride. The effects observed in guinea pigs and rats
were much milder (Kal’sada, 1964; Kurljandskij et al., 7.1.2.2 Liver
1968). Germanium tetrachloride had a pronounced Degenerative changes and necrosis, sometimes
irritating action on the conjunctivae of the eye in rats, associated with functional impairment (for example,
rabbits, and mice (Kal’sada, 1964; Kurljandskij et al., reduced detoxifying capacity—hippuric acid test),
1968). Local effects of germanium tetrachloride are were observed in acute, subacute, and chronic s­ tudies
very likely to be caused by a combined action of the by Kal’sada (1964) (mice: GeCl4 inhalation, 1.7-40 g/
compound and its hydrolysis products, such as GeO2, m3, single 2-h exposures; and 0.5-0.7 g/m3, 2 h/day,
HCl, and Ge2C16 (Kurljandskij et al., 1968). 40 days), by Kurljandskij et al. (1968) (rats: GeC14
inhalation, 0.30-0.7 g/m3, 4 h/day, 5 days/week, for
7.1.1.2 Humans 7 months), and by Gus’kova (1974) (rats and guinea
Mild irritation of the skin is produced by germa- pigs: GeH4 inhalation, 0.26-1.4 g/m3, single exposures
nium tetrachloride (Kal’sada, 1964). of 2 h for mice and 4 h for rats and other animals).
Increased incidence of fatty degeneration of the liver
7.1.2  Systemic Effects and Dose-Response (compared with controls) was found in rats after a life-
Relationships time exposure to 5 mg Ge/L as sodium germanate in
drinking water (Schroeder et al., 1968), but there was
7.1.2.1 Animals no effect in a similar experiment using mice (Schroeder
Inorganic germanium compounds seem to have a and Balassa, 1967b). Germanium was also found to
comparatively low systemic toxicity. The LD50 values of reduce chemically induced liver damage (see Section 8).
808 Larry S. Keith, Obaid M. Faroon, Nikki Maples-Reynolds, and Bruce A. Fowler

7.1.2.3 Kidney (2 g/m3 inhalation), 2 h for mice and 4 h for rats and
Degenerative changes in the epithelium of the other animals (Gus’kova, 1974) were accompanied
proximal tubules were noted by Kal’sada (1964), by various neurobehavioral signs (excitation, impair-
Kurljandskij et al. (1968), and Gus’kova (1974) ment of locomotor activity, listlessness, hypother-
after high-level inhalation exposure to germanium mia, and convulsions). The histochemical changes
tetrachloride and germanium hydride, respectively
­ observed by Kurljandskij et al. (1968) in the brain of
(for exposure conditions and animal species used, rats after chronic inhalation exposure to germanium
see Section 7.1.1) The same morphological changes, tetrachloride (3-7 mg/m3, 4 h/day, 5 days/week for
accompanied by proteinuria, occurred at a higher 7 months) are difficult to interpret.
incidence in rats exposed to sodium germanate The pathogenesis of neurological damage of GeO2 to
than in controls (Schroeder et al., 1968). Sanai the peripheral nerves in rats and monkeys was studied,
et al. (1991) treated rats with GeO2 for 24 weeks and but adverse effects were not observed. Exposure of rats
observed weight loss, decreased creatinine clear- orally to 100 mg/kg/day, 3 days/week for 8 weeks or i.p.
ance, increased blood urea nitrogen (BUN), and to 400 mg/kg/day, once a week for 8 weeks did not cause
increased serum phosphate. Morphological exami- degeneration of peripheral nerve myelin fibers. In addi-
nation revealed vacuolar degeneration of the distal tion, oral exposure of monkeys to 30 or 40 mg/kg/day,
convoluted tubules of the kidneys, ­electron-dense 5 days a week, for 8 months did not damage sural nerve
inclusions in the swollen mitochondria, and fibrous myelin fibers (Ohnishi et al., 1989). W
­ istar rats were simi-
connective tissue 16 weeks after cessation of the larly maintained on a diet containing 0.10% Ge as GeO2
treatment. High GeO2 deposition was observed in (average 100 mg/kg/day) for 8 months, resulting in seg-
the distal tubular epithelium at the end of the treat- mental demyelination/remyelination, neurocytic edema,
ment (24 weeks) and 16 weeks later (i.e. 40 weeks in disintegration of the cytoplasm, increased Schwann cell
total). Male albino guinea pigs fed 0.34% Ge as GeO2 volume, and deposition of electron-dense material within
for 2 months showed pathological and histochemical the mitochondria. These lesions suggest that the Schwann
degeneration of renal and muscle tissues associated cells are a primary target of Ge toxicity (Matsumuro et al.,
with electron-dense mitochondrial inclusions con- 1993).
taining Ge and reduced cytochrome c oxidase activ- Wu et al. (1992) and Yim et al. (1999) studies ultra-
ity (Yamasoba et al., 2006). structural/biochemical and histochemical changes
on muscles of rats treated with Ge for up to 24 weeks
7.1.2.4  Hematological Effects and reported a number of alterations in mitochondrial
enzyme functions, suggesting Ge mitochondrial tox-
Bailey et al. (1925) treated rabbits with GeO2 through icity as a model for understanding human mitochon-
repeated i.p. injections for 7 weeks with total doses of drial myoencephalopathy.
28-280 mg/kg, and Rochow and Sindler (1950) treated The effect of germanium on hearing was studied.
rabbits and hamsters, dimethylgermanium oxide, sin- Yamasoba et al. (2006) fed male albino guinea pigs
gle and repeated subcutaneously doses up to 1 g Ge/kg with normal auditory brain stem response (ABR)
and reported no hematological effects. Similarly, mul- thresholds 0.10% Ge (as GeO2) for 6 months or 0.34%
tiple i.p. doses of sodium germanate (100 mg/kg) and Ge for 2 months. ABRs were measured as cochlear
repeated oral doses of neutralized GeO2 (0.9-170 mg/ waveform responses to 2, 4, 8, or 16 kHz pure tone
kg body weight) also had no hematological effects in bursts via implanted electrodes. Animals receiving the
rats (Rosenfeld and Wallace, 1953). Some changes in higher dose showed increased ABR thresholds at each
the blood of uncertain biological significance, such as frequency and significant degeneration and abnor-
increased hemoglobin and increased numbers of eryth- mal mitochondrial inclusions in stria vascularis cells
rocytes and leukocytes, were observed by Kurljandskij of the organ of Corti. In a follow-up study, Yamasoba
et al. (1968) (rats: GeC14 inhalation, 3-7 mg/m3, 4 h/ et al. (2007) fed guinea pigs 0%, 0.15%, or 0.5% GeO2
day, 5 days/week for 7 months) and Gus’kova (1974) for 6 months; the low dose resulted in no impact on
(rats and guinea pigs: GeH4 inhalation, 50-250 mg/m3, ABR, whereas the high dose induced approximately
4 months). 40 dB increase in the ABR threshold within 2 months
of exposure. Mice appear to be more sensitive. CBA
7.1.2.5  Nervous System mice fed 0.15% GeO2 for 3 months experienced pro-
Lethal exposures of rats to GeO2 (600-1200 mg/kg, found hearing loss. Yamasoba et al. (2007) reviewed
single i.p. dose (Rosenfeld and Wallace, 1953) and of the total available research on age-related hearing
mice to germanium tetrachloride (20-40 g/m3, inha- loss (AHL) conducted in their laboratory and by other
lation 2 h) (Kal’sada, 1964) and germanium hydride groups, postulating that AHL is mainly the result of a
 37 Germanium 809

reduction in metabolism caused by the accumulation 5 mL of viral culture (1 × 106.1 50% tissue culture infec-
of mitochondrial DNA mutations and deletions plus tive per mL). Rectal temperature measurements were
declining respiratory chain function. unchanged in the GB group and significantly elevated
The impact of GeO2 on the ascending auditory path- in the control group. Animals were sacrificed at 12 and
way was evaluated in male Wistar rats exposed to 0, 28 days postinoculation and lung and lymphoid tis-
68, and 372 mg Ge/kg/day as GeO2 in drinking water sues were evaluated. Relative to controls, the GB group
and monitored after 2 and 4 weeks. Exposure resulted at 12 days postinoculation had significantly decreased
in significant dose- and time-dependent effects on stria viral titers and less severe histopathological changes in
vascularis nuclear activity and brainstem transmission, all tissues tested (lung, tonsils, thymus, and bronchial
seen as increases in brain auditory stem evoked poten- lymph nodes), as well as milder cases of interstitial
tial (BAEP) threshold (23-77%), prolonged BAEP laten- pneumonia (Jung et al., 2013).
cies, and increased BAEP interpeak latencies (IPLs) for 7.1.2.6.3  Cell Cycle  Chiu et al. (2002) reported that
all four wave forms, resulting in hearing loss in the rats in vitro exposure of Chinese hamster ovary (CHO)
(Lin et al., 2009a). cells to germanium oxide inhibited the G2 to M phase.
The mechanism of action for Ge-induced neurologi- These changes occurred at Ge concentrations up to
cal damage was studied in vitro in the mouse neuro-2A 5 mmol/L after 12 h of exposure but decreased at con-
neuroblastoma cell line. Exposure to GeO2 concentra- centrations > 5 mmol/L. Examination of cells labeled
tions of 0-800 μM resulted in dose- and time-related with 5-bromodeoxyurindine showed a dose-related
effects, with exposures as low as 1 μM for 72 h result- delay in progression from S phase. The authors exam-
ing in an increased release of cytochrome c, reduced ined cyclin content and cyclin-dependent kinase activ-
mitochondrial cell potential, translocation of Bax, and ity and found that cyclin B1 levels were not altered but
reduced Bcl-2 expression, resulting in mitochondria- that cyclin-dependent kinase 1 (CDK1) activity was
mediated cellular apoptosis (Lin et al., 2006). decreased; this was restored after 9 h in control media
resulting in resumption of G2-M phase transition.
7.1.2.6  Other Effects 7.1.2.6.4  Genotoxicity The viability of CHO K1
7.1.2.6.1  Body Weight  Arts et al. (1994) studied cells was found to slightly increase after 12-h exposure
the acute and subacute toxicity of germanium oxide to 5 mM (0.36 mg/mL) small-sized Ge metal nanopar-
in Wistar rats of each sex after inhalation exposure ticles (1-10 nm), but it was significantly reduced to
to either amorphous or hexagonal germanium oxide 80% and 90% by respective exposure to 5 mM GeO2 or
over a dose range from 0 to 309 mg/m3 for 6 h/day medium-sized nanoparticles (20-50 nm). Coexposure
5 days per week for 4 weeks. Two additional groups of each substance with ionizing radiation (1.5 Gy of
of rats of each sex were kept for 33 days after cessation 135 kVp X-rays) greatly reduced viability to approxi-
of exposure to either 0 or 309 mg/m3 doses to assess mately 20-30% (Lin et al., 2009b). Lin et al. (2009b) also
recovery. At the end of the study, a number of major compared the effect of 5 mM GeO2 or Ge-132 for 12 h
organs showed increased weights and histopathologi- followed by 0 or 20 Gy of X-rays on CHO cell viabil-
cal changes. These were accompanied by alterations ity. Cell viability for the Ge-132 group was compara-
in serum clinical chemistries. These toxic alterations ble to controls; however, it was significantly reduced
were found to persist in the treatment groups after the for the GeO2 group. Radiosensitization was observed
33-day recovery period. after treatment of CHO K1 cells with 5 mM germa-
7.1.2.6.2  Immunological Effects Germanium bio- nium oxide and 0.36 mg/mL nanometer-sized ger-
tite (GB), an aluminosilicate mineral containing 36 ppm manium particles (Lin et al., 2009b). Cell viability was
Ge, was studied as a feed supplement and found to not affected by treatment; however, irradiation with
enhance immunological protection in mice and to 20 Gy X-ray caused DNA strand breaks (shown using
effectively treat porcine reproductive and respiratory the alkaline comet assay). DNA repair (Olive moment)
system virus (PRRSV). Female BALB/c mice, eight per was inhibited with both germanium treatments, with
group, were fed chow supplemented with 0, 0.15%, or higher levels observed with the nanoparticles. Levels
0.3% GB for 2 weeks. Their spleens were then removed of γ-H2AX, , a phosphorylated member of the H2A his-
and incubated with or without concanavalin A (ConA) tone protein family, in germanium nano-treated cells
or lipopolysaccharide (LPS) mitogens. GB supplemen- were not elevated; however, after radiation treatment
tation at both levels was found to significantly enhance there was a twofold increase (Lin et al., 2009a).
lymphocyte proliferation in response to ConA, but not In the same laboratory, CHO K1 cells were treated
to LPS. Twelve pigs, six per group, were fed a stan- with up to 3 μM water-soluble allyamine-coated germa-
dard diet supplemented with 0% and 0.3% GB; all were nium nanoparticles for 4 h (Ma et al., 2011). In this study,
then infected with PRRSV by intranasal exposure to an MTT [3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl
810 Larry S. Keith, Obaid M. Faroon, Nikki Maples-Reynolds, and Bruce A. Fowler

tetrazolium bromide] assay showed cytotoxicity at the studies addressed in this section were conducted
concentrations greater than 3  μM. Flow cytometry to address health benefits, e.g. as health supplements
demonstrated the sub-G1 fraction was absent, with or cancer treatments. However, subsequent to the pub-
no alteration in cell cycle parameters, indicating that lication of those studies, both the American Cancer
Ge nanoparticles do not induce apoptotic cell death. Society (ACS, 2011) and the FDA concluded that ger-
However, necrotic cell death signals were detected in manium compounds are harmful, and the FDA (1995,
treated cells, including increased intracellular calcium 2004, 2011) no longer allows their import.
and reactive oxygen species and decreased mitochon- In 1988, the FDA accepted the use of germanium
drial membrane potential (Ma et al., 2011). sesquioxide as a food additive, but in 1995 they issued
The cytotoxicity of GeCl4 was studied in vitro and an import alert to remove the food additive on the
in vivo and found to be low. Immortalized human basis of its renal toxicity (FDA, 1995). In October 2003,
skin keratinocyte (HaCaT) cells exposed to 10-700 μM the FDA refused an entry of 20 kg bulk Ge sesquioxide
GeC14 showed a very low level of cytotoxicity, while in human dietary supplements because germanium
fibroblasts extracted from Balb/3T3 mice 3 days after had caused nephrotoxicity (kidney injury) and death
i.p. exposure to 20 mg GeC14 (80 ng Ge/kg) showed when used chronically by humans, even at the recom-
a slight dose-related increased inhibition of colony- mended levels of use (FDA, 2004).
forming efficiency (Sabbioni et al., 2010). In 2011, the FDA found that germanium-­containing
7.1.2.6.5  Connective Tissue  Ozeki et al. (2006) products were still being labeled for human use
studied the toxicity of germanium apatite in gingi- and imported even though they were recognized
val fibroblasts and reported that the cellular growth to induce health effects at the doses recommended
rate was almost that of controls at a concentration of by the providers. Such labeling was not consid-
0.1 mg/mL, but that the growth rate was attenuated at ered appropriate, and the FDA had not issued any
1.0 mg/mL. The observed growth rate was increased new drug applications or investigational new drug
at 1.0 mg/mL when the pH of the cell growth medium applications for germanium products. For these
was adjusted to 7.60. reasons, the FDA reissued Important Alert 54-07 to
inform FDA field personnel why and how to detain
7.1.3 Humans any ­germanium product “if the product claims to
be useful in the diagnosis, cure, mitigation, treat-
Humans have been shown to experience adverse ment, or prevention of disease.” Examples of those
health effects associated with high exposures to ger- products include ­ germanium sesquioxide, GE-132,
manium compounds. ­GE-OXY-132, ­Vitamin “O,” ­Pro-Oxygen, Nutrigel 132,
Immune Multiple, and Germax (FDA, 2011), some of
7.1.3.1  Occupational Exposures
which were the subject of studies addressed in this
Swennen et al. (2000) reported some clinical renal chapter. Germanium substances for nonhuman use,
differences between occupationally exposed germa- e.g. in semiconductors, are exempt.
nium workers and control workers. These included Similarly, the ACS concluded that germanium sup-
slightly higher than control levels of low molecular plements may be harmful to humans and may interfere
proteins (microglobulin, retinol-binding protein, and with medicines. The ACS recommends against their
kallikrein) in urine samples of the Ge-exposed work- use and cautions that using germanium “treatment
ers relative to controls. In addition, the mean albumin alone and avoiding or delaying conventional medical
and transferrin concentrations were also significantly care for cancer may have serious health consequences”
increased in exposed workers compared with controls. (ACS, 2011).
In the exposed group, the prevalence of increased 7.1.3.2.1 Kidney  A case report indicated that a
albumin (>  17.6 
mg/g creatinine) and transferrin 53-year-old man who took a total of 400 g germanium
(> 832 μg/g creatinine) were also significantly higher oxide as a health supplement over 14 months result-
than in the control group (12.0 vs. 1.3%, P = 0.006 and ing in weight loss (16 kg in 3 months), azotemia (BUN
20 vs. 8.9%, P = 0.04, respectively). The authors con- 60 mg/dL, creatinine 2.6 mg/dL), and asthenia (pri-
cluded that the increase in urinary levels of albumin marily of the lower extremities); 2 months later his
and transferrin probably reflect glomerular changes in condition degraded further and he was admitted to the
the kidneys. hospital with chronic renal failure. Histological exam-
ination of the kidneys revealed no antibody deposits,
7.1.3.2  Germanium Food Supplements lipofuscin accumulation, or vacuolar degeneration,
Germanium-containing substances have been but some cell death (Kim et al., 1998). In Europe,
advertised as being protective of human health, and ­germanium has been marketed as an ingredient in
 37 Germanium 811

nonprescription drugs and recommended by distrib- months as a remedy (Nagata et al., 1985; Obara et al.,
utors for AIDS and cancer treatment. However, the 1991; Okada et al., 1989; Omata et al., 1986; Sanai et al.,
use of Ge for these purposes is not approved by regu- 1990a,b; Schauss, 1991a,b). Schauss (1991a,b) and Tao
latory agencies in most European countries. In Japan, and Bolger (1997) summarized the literature on human
it is used as an elixir to maintain or restore health. Ge toxicity from dietary supplements and reported
Asaka et al. (1995) reported a case of sensory ataxia approximately 23 cases of germanium-related toxicity
in a patient who took an inorganic Ge compound at worldwide; 21 of these cases involved Japanese users.
a dose of 36 mg/day for approximately 6 years. Gait The duration of intakes ranged from 4 to 24 months,
disturbances, irreversible peripheral neuropathy, and with doses varying between 14 and 324 g germanium
renal damage were observed. At autopsy, the patient compounds.
presented with degenerative changes of the dorsal 7.1.3.2.2  Neurological  Neuropathy mainly involving
root ganglia and dorsal column of the spinal cord. the sensory nerves was demonstrated in a 53-year-old
The neurodegenerative changes seemed to be more man who took 400 g germanium oxide as a health sup-
directly related to Ge toxicity rather than secondary plement over 14 months (Kim et al., 1998). Observa-
to uremia because the renal changes were more mod- tions included grade IV motor strength, negative deep
est in nature. tendon reflex in the lower extremities, and persistent
A patient with a germanium hair level of 175 ppm tingling sensation of the palms and soles. A 63-year-
showed variation in the fiber sizes of the skeletal old woman consumed 36 mg inorganic germanium/
muscles, with dense cytoplasmic bodies, reduction of day for 6 years (total dose equivalent 80 g) and sub-
cytochrome c oxidase activity, mitochondrial myopa- sequently developed difficulty in writing, gait disco-
thies, and vacuolar degeneration. Similar findings ordination, and peripheral neuropathy. The neuronal
were observed in rats treated with germanium oxide damage was manifest as irreversible, and an autopsy
(Higuchi et al., 1989). showed degeneration of dorsal root ganglion cells and
Takeuchi et al. (1992) reported a case of a 55-year-old degeneration of the dorsal column of the spinal cord.
woman who ingested a total dose of 49 g Ge over a The patient died from sepsis and pneumonia (Asaka
prior 19-month period. She presented with increased et al., 1995).
BUN and serum creatinine values and evidence of dis- 7.1.3.2.3  Cardiovascular Effects  Human ingestion
tal tubular damage without glomerular and vascular of 30 g GeO2 in capsule form as a remedy over 8 months
changes at autopsy. These data suggest that the distal resulted in remarkable cardiac dilation, vacuolar
tubular epithelium is also a target cell population for degeneration of myocardial cells, and interstitial edema
Ge toxicity. (Matsusaka et al., 1988). Lee et al. performed toxicity
After 2 months ingestion of elemental germanium studies on the human health supplement, Geranti Bio
(total dose 25 g) by a 43-year-old white woman, severe Ge®, and organic germanium-fortified yeasts at single
lactic acidosis, renal failure, and hepatotoxicity devel- (2000 mg/kg) and repeated (0, 500, 1000, 2000 mg/kg)
oped. Autopsy findings were hydropic degeneration daily oral doses in water for 13 weeks in beagle dogs
and the presence of inclusion bodies in the proximal (Lee et al., 2004a) and in rats (Lee et al., 2004b). They
convoluted tubules; however, the renal glomeruli and observed some alterations in blood chemistry, hema-
the renal interstitial tissue seemed normal and unaf- tology, and heart R-R interval and QT correction in
fected. Extensive steatosis of the liver was observed, male, but not in female, dogs, and an increase in rela-
in addition to a high level of germanium in urine, tive heart rate in both males and females at the highest
blood, kidneys, liver, muscles, and pancreas (Krapf dose. Only mild histological alterations were observed
et al., 1992). There was a case report of a 58-year-old in major organ systems.
man who consumed 426 g germanium-lactate-citrate
(Ge content 18% by weight) over 6 months as a natural
7.2  Organometallic Compounds
remedy. He lost 10 kg in weight (resulting in a body
weight of 64 kg) and suffered from nausea, yellowish The toxicity of several trialkylgermanium com-
skin, and uremia. Blood chemistry indicated increased pounds was studied by Cremer and Aldridge (1964).
sedimentation rate, normal leukocyte count, reduced Triethylgermanium acetate was toxic to rats at i.v. doses
erythrocyte and thrombocyte counts, and electrolyte of 50 mg/kg body weight, and orally at 250 mg/kg.
levels that were close to the lowest part of the normal Tri-N-butylgermanium acetate was tolerated orally in
range (Luck et al., 1999). This patient survived after single doses of up to 375 mg/kg. The toxicity of trial-
long medical intervention. Similar kidney lesions and kylgermanium compounds was less than one-tenth
renal failure were described on autopsy in a patient of the toxicity of triethyltin or triethyllead and did
who died after a daily intake of 600 mg of GeO2 for 18 not seem to have a predominant effect on the central
812 Larry S. Keith, Obaid M. Faroon, Nikki Maples-Reynolds, and Bruce A. Fowler

nervous system. Among the tetraalkylgermanium 7.3  Carcinogenicity, Mutagenicity, and

compounds evaluated by Caujolle et al. (1966), the Teratogenicity
least toxic were those with saturated normal sym-
metrical radicals. The halogenation of organic radicals As the development and use of semiconductors
increased the biological activity. Higher hexaalkyl- increased during the 1980s and 1990s, antimony, gal-
digermanium oxides (butyl-, amyl-, hexyl-) were less lium, germanium, selenium, and thallium were iden-
toxic than the ethyl homologs (Bouissou et al., 1964). tified as having carcinogenic potential and increased
Spirogermanium was neurotoxic to human cancer research into these effects was recommended (Fowler
patients after i.v. administration in doses from 32 to et al., 1993). Subsequent studies have found germa-
160 mg/m2. The reversible effects included lethargy, nium not to induce such effects but rather to have anti-
vertigo, ataxia, and grand mal seizures (at high doses). tumorigenic properties.
Neurotoxic effects were also observed in dogs (Schein Studies by Kanisawa and Schroeder (1967) on mice
et al., 1980). Another organogermanium antitumor and by Schroeder et al. (1968) on rats (lifetime expo-
agent, carboxyethyl Ge sesquioxide, was considered to sure to 5 mg Ge/L in drinking water as sodium germ-
restore the impaired immune response in aged C3A/ anate) did not produce any evidence of carcinogenicity
HeJ mice (Mizushima et al., 1980). This compound was of Ge compounds.
found to induce hypotension and bradycardia in rats There is no definite evidence for mutagenicity of Ge
by promoting activation of the parasympathetic effer- compounds, although Ge tetrachloride was positive in
ent and inhibition of the sympathetic efferent inputs the rec-assay (Kanematsu and Kada, 1978). Spiroger-
(Ho et al., 1990). manium inhibits DNA and RNA synthesis in HeLa
Lin et al. (2009b) evaluated the effect of exposure cells and is cytotoxic in vitro (Schein et al., 1980).
to the Ge-132 health supplement, GeO2, or Ge metal Dimethylgermanium oxide, an analog of acetone,
nanoparticles (at 0.5-22 mM concentrations), for vari- was shown to produce a variety of malformations in
ous exposure times (1, 2, 4, 8, 12 h), either with or chick embryos after incubation for 72 and 96 h, with
without coexposure to ionizing radiation (1.5-20 Gy), the amount required for 50% of its maximum activ-
on survival, growth, and colony formation in CHO ity (ED50) being 1.8 and 2.5 mg/embryo, respectively,
K1 cells. In each case, cellular responses were compa- compared with 17.9 and 25.1 mg/embryo for acetone
rable to controls for Ge-132 but adverse for GeO2 and (Caujolle et al., 1965). Ferm and Carpenter (1970) did
Ge nanoparticles. However, it is curious that none not find any teratogenic or fetotoxic effects in hamsters
of the several evaluations conducted in this study treated with sodium germanate (40-100 mg/kg, i.v.
included all three substances. Exposure of cells for injection, 8-day gestation). Hatano et al. (1981b) did not
12 h to 5 mM of each substance followed by a 1.5 Gy observe any adverse effect of Ge dioxide (19, 38, and
X-ray dose reduced cell viability by 20% for Ge-132 75 mg/kg, subcutaneously, pregnant rats) on mothers,
(comparable to controls) but by 70-80% for GeO2 and embryos, or newborns. Ge oxide at 0.05 or 0.1 mg/kg
Ge nanoparticle exposure. Increasing the X-ray dose inhibits the dose-related increase in frequency of sperm
to 3 Gy resulted in the almost complete elimination with abnormal head morphology after treatment with
of GeO2-exposed cells, indicating that this substance cadmium chloride in mice. However, germanium
sensitizes cells to radiation. DNA repair efficiency oxide alone did not affect the frequency of sperm head
was studied using the same 5-nM exposures limited abnormalities (Han et al., 1992).
to GeO2 and nanoparticles followed by a 4-h repair Germanium in cationic form did not induce neoplastic
period. Each treatment temporarily delayed cellular lesions and showed no potential for carcinogenicity on
repair at the G2/M phase, with a longer delay for BALB/c3T3 mouse embryo fibroblasts exposed in vitro
nanoparticles. This finding, along with the obser- to 10-700 μM GeCl4 for 10 days (Sabbioni et al., 2010).
vation by microscopy that some Ge nanoparticles Neither the National Institute of Environmen-
remained attached to cell surfaces even after sev- tal Health Sciences nor the International Agency for
eral washes, indicated that Ge nanoparticles can be Research on Cancer have assigned a cancer classifica-
more damaging than GeO2 to DNA. The impact of tion to germanium (NTP, 2011; IARC, 2013).
Ge nanoparticles on DNA was evaluated by exposing
cells to a 5 mM concentration for 12 h followed by 0
or 20 Gy X-rays, and then observing the formation of 8  CANCER AND OTHER TREATMENT
γ-H2AX in chromatin. Foci of γ-H2AX appeared only
with coexposure to a high radiation dose, indicating Spirogermanium has been studied historically for
that Ge nanoparticles by themselves do not cause its potential therapeutic use in, for example, suppres-
DNA damage (Lin et al., 2009b). sion of experimental autoimmune encephalomyelitis
 37 Germanium 813

(Sacks et al., 1987); antiarthritic and immunoregula- s­ pirulina, or the spirulina diet containing 30 ppm Ge
tory activity (DiMartino et al., 1986); induction of sup- as GeO2. ­ Hepatitis was then induced (through i.p.
pressor cells in the splenic cell population and the injection of d­ -galactosamine and lipopolysaccharide).
exhibited antiarthritic and immunoregulatory effects The following day, samples were collected. Compared
(Badger et al., 1985); as a treatment for advanced renal with the control or spirulina-only groups, levels of
cell cancer (Saiers et al., 1987), advanced non-small serum analytes in the germanium group were signifi-
cell lung cancer (Dhingra et al., 1986), and similar cantly lower (plasma alanine transaminase, aspartate
therapies (Schulman et al., 1984; Volgelzang et al., aminotransferase and lactate dehydrogenase), showed
1985); ascites tumors in mice (Suzuki et al., 1986); and inhibited increases [plasma interferon gamma (IFN-γ),
advanced colorectal cancer (McMaster et al., 1990). In tumor necrosis factor (TNF-α), catalase, and GPx), or
the latter, none of the patients had complete recov- increased ­interleukin-10 (IL-10)]. Together, these indi-
ery, all patients had severe treatment-related toxicity, cated that pre-exposure to germanium might protect
two deaths occurred, and five patients were removed the liver from hepatitis (Yoshinari et al., 2013).
from the treatment because of intolerable side effects. Mixed-sulfonated aluminum phthalocyanine (AlPc-
The spirogermanium toxicity includes paresthesias, Smix) is a commercially available photosensitizer for
dizziness, and neutropenia that required hospitaliza- cancer photodynamic therapy (PDT). Germanium and
tion. The therapeutic use of spirogermanium has been a hydrogen analog control (GePcSmix and H2PcSmix)
discontinued because of its high toxicity and the low were applied to human SNO esophageal carcinoma
response rate. As addressed above, the FDA and the cells. GePcSmix exposure decreased cell viability and
ACS, respectively, recommend against treating indi- increased cell inflammation more effectively than the
viduals with germanium compounds or delaying control and used processes of apoptosis and necrosis,
conventional medical cancer care to use germanium- both of which indicate that this compound might be
containing substances. an effective PDT agent (Seotsanyana-Mokhosi et al.,
Kang et al. (2001) studied the anticancer effect 2006).
of GeO2 in F344 rat liver epithelial cells exposed to
12-O-tetradecanoylphorbol-13-acetate (TPA). These
authors identified TPA as a tumor promoter, although References
a long-term rat study by Klein-Szanto et al. (1986) did ACS (American Cancer Society), 2011. Germanium. American
not reach this conclusion and TPA is being studied ­Cancer Society. Available at http://www.cancer.org/treatment/
in the treatment of leukemias and lymphomas (UAz, treatmentsandsideeffects/complementaryandalternativemedicine/
herbsvitaminsandminerals/germanium (accessed 15.12.13.).
2013). Cell treatment with 10 μg/L TPA for 1 h inhib-
Aldridge, W.N., 1978. In: Giden, M., Harrison, P.G. (Eds.), The
ited gap junction intercellular communication; how- ­Organometallic and Coordination Chemistry of Germanium, Tin
ever, pretreatment overnight with GeO2 prevented and Lead. Freund Publishing House, Tel-Aviv, Israel, pp. 9–30.
gap junction inhibition by decreasing the ratio of phos- Ali, M.M., Noaman, E., Kamal, S., et al., 2007. Acta. Pharm. 57 (1),
phorylation bands (P2/P0) in Western blot analyses. 1–12.
Amos, M.D., Willis, J.B., 1966. Spectrochim. Acta. Part E 22, 1325–1343.
This indicates that GeO2 can prevent the hyperphos-
ANSES (French Agency for Food, Environmental and Occupational
phorylation of Cx43 by tumor promotors and thus act Health & Safety), 2011. Second French Total Diet Study (TDS 2)
as a cancer preventative (Kang et al., 2001). Report 1 Inorganic contaminants, minerals, persistent organic
Germanium was found to protect the liver and pollutants, mycotoxins and phytoestrogens. French Agency
body of male Swiss albino rats against the free radi- for Food, Environmental and Occupational Health and Safety,
­Maisons-Alfort, France.
cal toxicity of a potentially lethal 6.5 Gy whole-body
Arts, J.H., Til, H.P., et al., 1994. Food Chem. Toxicol. 32, 1037–1046.
dose of ionizing radiation. The compound, germanium Asaka, T., Ntta, E., Makifunchi, T., et al., 1995. J. Neurol. Sci. 130 (2),
dichlorotetrakis(l-cysteinyl-alpha-tocopherol amide) 220–223.
dichloride, was administered i.p. as six 75 mg/kg Aso, H., Suzuki, F., Ebina, T., et al., 1989. J. Biol. Response. Mod. 8,
doses prior to 6.5 Gy gamma irradiation. Pretreatment 180–189.
Badger, A., Mirabelli, C., DiMartino, M., 1985. Immunopharmacol-
with germanium was found to improve blood and
ogy 10, 201–207.
liver levels of lipoprotein X (LPx); normalize levels of Bailey, G.H., Davidson, P.B., Bunting, C.H., 1925. J. Am. Med. Assoc.
superoxide dismutase (SOD), GPx, and catalase (CAT); 84, 1722–1724.
and reduce levels of blood triglycerides and choles- Beche, A., Rouviere, J.L., Barnes, J.P., et al., 2013. Ultramicroscopy
terol, indicating it might have radioprotective proper- 131, 10–23.
Bonardi, M., Birattari, C., Gilardi, M.C., et al., 1982. J. Radiol. Anal.
ties (Ali et al., 2007).
Chem. 70, 337–398.
Germanium was found to reduce chemically Bouissou, H., Caujolle, D., Caujolle, F., et al., 1964. C. R. Acad. Sri.
induced liver damage. Male Wistar rats were fed Skr. D. 259, 3408–3410 (in French).
a basal diet, the same diet supplemented with 5% Braman, R.S., Tompkins, M.A., 1978. J. Anal. Chem. 50, 1088–1093.
814 Larry S. Keith, Obaid M. Faroon, Nikki Maples-Reynolds, and Bruce A. Fowler

Brown, R., Taylor, H.E., 1975. Trace Element Analysis of Normal Gus’kova, E.I., 1974. Gig. Tr. Prof. Zabol. 2, 56–57 (in Russian).
Lung Tissue and Hilar Lymph Nodes by Spark Source Mass Hamilton, E.I., Minski, M.J., 1972. Sci. Total Environ. 1, 104–107.
Spectrometry. HEW Publication No. NIOSH 75-129. National Hamilton, E.I., Minski, M.J., 1972/1973. Sci. Total Environ. 1,
­Institute for Occupational Safety and Health, U.S. Department of 375–394.
Health, Education and Welfare, Cincinnati. pp. 13–31. Hamilton, E.I., Minski, M.J., Cleary, J.J., 1972. Sci. Total Environ. 1,
Budman, D.R., Schulman, P., Vinciguerra, V., et al., 1981. Proc. Am. 1–14.
Assoc. Cancer Res. Clin. Oncol. 22, 362. Hamilton, E.I., Minski, M.J., Cleary, J.J., 1972/1973. Sci. Total
Burger, C., Goerres, G., Schoenes, S., et al., 2002. Eur. J. Nucl. Med. ­Environ. 1, 341–374.
Mol. Imaging 29 (7), 922–927. Han, C., Wu, G., Yin, Y., et al., 1992. Food Chem. Toxicol. 30 (6),
Caujolle, F., Caujolle, D., Magna, H., 1963. C. R. Acad. Sri. Skr. D. 257, 521–524.
1563–1565 (in French). Hatano, M., Ishimura, K., Fuchigami, K., 1981a. Oyo Yakuri 21 (5),
Caujolle, F., Caujolle, D., Cros, S., et al., 1965. Bull. Trav. Soc. Pharma- 793–796 (in Japanese).
cal. Lyon 7, 221–235 (in French). Hatano, M., Ishimura, K., Fuchigami, K., 1981b. Oyo Yakuri 21 (5),
Caujolle, F., Caujolle, D., Dao-Huy-Giao, et al., 1966. C. R. Acad. Sci. 797–807 (in Japanese).
Str. D. 262, 1302–1304 (in French). Higuchi, I., Izumo, S., Kuriyama, M., et al., 1989. Acta. Neuropathol.
Changizi, V., Kheradmand, A.A., Oghabian, M.A., 2008. J. Med. 79, 300–304.
Phys. 33 (1), 19–23. Ho, C., Chern, Y., Lin, M., 1990. Pharmacology 41, 286–291.
ChemIDplus, 2013. Germanium. Available at http://chem.sis.nlm. IARC (International Agency for Research on Cancer), 2013. Agents
nih.gov/chemidplus/ProxyServlet?objectHandle=DBMaint&act Classified by the IARC Monographs, Volumes 1–109. I­ nternational
ionHandle=default&nextPage=jsp/chemidlite/ResultScreen.jsp Agency for Research on Cancer. World Health Organization.
&TXTSUPERLISTID=0007440564 (accessed 15.12.13). Available at http://www.iarc.fr/en/publications/list/mono
Chiu, S.J., Lee, M.Y., Chen, H.W., et al., 2002. Chem. Biol. Interact. graphs/index.php (accessed 14. 03.14).
141 (3), 211–228. Jao, S.W., Lee, W., Ho, Y.S., 1990. Dis. Colon. Rectum. 33, 99–104.
Coal Research Section (1972). “Mineral Matter and Trace Elements Johnson, D.J., West, T.S., Dagnall, R.M., 1973. Anal. Chim. Acta. 67,
in U.S. Coals.” College of Earth and Mineral Sciences, The 79–87.
­Pennsylvania State University. Report submitted to the Office Jonson, R., Roos, B., Hansson, T., 1986. Acta. Radiol. Diagn. 27,
of Coal Research, U.S. Department of the Interior, Contract No. 105–109.
14-01-0001-390, Washington, D.C. Jung, B.G., Lee, J.A., Lee, B.J., 2013. J. Vet. Sci. 14 (2), 135–141.
Cotton, F., Wilkinson, G., 1988. Advanced Inorganic Chemistry, Kakimoto, N., Miyao, K., 1979. Jpn. Kokai. Tokyo Koho. 79, 160–742
fifth ed. John Wiley & Sons, New York. (in Japanese).
Cremer, J.E., Aldridge, W.N., 1964. Br. J. Ind. Med. 21, 214–217. Kal’sada, I.N., 1964. Gig. Tr. Prof. Zabol. 4, 57–60 (in Russian).
Dhingra, H., Umsawasdi, T., Chiuten, D., et al., 1986. Cancer Treat. Kanematsu, K., Kada, T., 1978. Mutat. Res. 53, 207–208.
Rep. 70 (5), 673–674. Kang, K., Yun, J., Yoon, B., et al., 2001. Cancer Lett. 166 (2), 147–153.
DiMartino, M., Lee, J., Badger, A., et al., 1986. J. Pharmacol. Exp. Kanisawa, M., Schroeder, H.A., 1967. Cancer Res. 27, 1192–1195.
Ther. 236 (1), 103–110. Kenney, D., 1980. Cosmet. Toiletries 95 (11), 58.
Dudley, H.C., 1953. AMA. Arch. Ind. Hyg. Occup. Med. 8, 528–530. Kim, K., Lim, C., Kim, S., et al., 1998. Nephrol. Dial. Transplant. 13,
Dudley, H.C., Wallace, E.J., 1952. AMA. Arch. Ind. Hyg. Occup. Med. 3218–3219.
6, 263–270. Klein-Szanto, A.J., Conti, C.J., Aldaz, C.M., Clapp, N., Nesnow, S.,
FDA (U.S. Food and Drug Administration). (1995). “Import Alert Slaga, T.J., 1986. Environ. Health Perspect. 68, 75–80.
#54–07: Germanium products. The Drugs, Devices, and Biologics Kobayashi, A., Ogra, Y., 2009. J. Toxicol. Sci. 34 (3), 295–303.
SDWG,” U.S. Food and Drug Administration, Washington, DC. Kopp, P., Bergmann, H., Havlik, E., et al., 1994. Health Phys. 67,
Available at http://www.fda.gov/ora/fiars/ora_import_ia5407. 616–620.
html. Krapf, R., Schaffner, T., Iten, P., 1992. Nephron 62, 351–356.
FDA, 2004. Statement of Robert E Brackett, Ph.D., Director, Krystek, P., Ritsema, R.J., 2004. Trace Elem. Med. Biol. 18, 9–16.
­Center for Food Safety and Applied Nutrition, Food and Drug Kumano, N., Nakai, Y., Ishikama, T., et al., 1978. Sci. Rep. Res. Inst.
­Administration before the Committee of Government Reform Tohoku Univ. Ser. C. 25 (3/4), 89–95.
Subcommittee on Human Rights and Wellness, United States Kurljandskij, B.A., Klockova, S.I., Masbic, F.D., et al., 1968. Gig. Tr.
House of Representatives. U.S. Food and Drug Administration, Prof. Zabol. 12, 51–53 (in Russian).
Washington, DC. Lee, H., Trevors, J., Dyke, M., 1990. Biotech. Adv. 8, 539–546.
FDA. (2011). “Import Alert #54–07: Germanium Products.” U.S. Lee, J.S., Park, J.I., Kim, S.H., et al., 2004a. J. Toxicol. Sci. 29 (5),
Food and Drug Administration, Washington, DC. Available at 555–569.
http://www.accessdata.fda.gov/cms_ia/importalert_139.html. Lee, J.S., Park, J.I., Kim, S.H., et al., 2004b. J. Toxicol. Sci. 29 (5),
Accessed 15 December, 2013. 541–553.
Ferm, V.H., Carpenter, S.J., 1970. Toxicol. Appl. Pharmacol. 16, 166–170. Lim, D.H., Li, M., Seo, J.A., et al., 2010. Bioorg. Med. Chem. Lett.
Fowler, B.A., Yamauchi, H., Conner, E.A., et al., 1993. Scand. J. Work 20 (14), 4032–4034.
Environ. Health 19 (Suppl 1), 101–103. Lin, C.H., Chen, T.J., Hsieh, Y.L., et al., 1999. Toxicology 132, 147–153.
FSA (Food Standards Agency), 1997. Food surveillance summary Lin, C.H., Chen, S.S., Lin, Y.C., et al., 2006. Neurotoxicology 27 (6),
sheet No. 131: MAFF UK 1994 total diet study: metals and other 1052–1063.
elements. Available at http://archive.food.gov.uk/maff/archive/ Lin, C.H., Chen, T.J., Chen, S.S., 2009a. Toxicology 256 (1-2), 110–117.
food/infsheet/1997/n0131/131tds.htm#Table2. Lin, M.H., Hsu, T.S., Yang, P.M., et al., 2009b. Int. J. Radiat. Biol. 85
Fyfe, W.S., 1974. Geochemistry. Clarendon Press, Oxford. 8. (3), 214–226.
Goldman, Z.I., 1960. Gig. Tr. Prof. Zabol. 10, 30–35 (in Russian). Luck, B.E., Mann, H., Melzer, H., et al., 1999. Nephrol. Dial. Trans-
Goerres, G.W., Ziegler, S.I., Burger, C., et al., 2003. Radiology 226 (2), plant. 14, 2464–2468.
577–584. Luke, C.L., Campbell, M.E., 1956. Anal. Chem. 28, 1273–1276.
 37 Germanium 815

Ma, Y.H., Huang, C.P., Tsai, J.S., et al., 2011. Toxicol. Lett. 207, Sabbioni, E., Fortaner, S., Bosisio, S., et al., 2010. J. Appl. Toxicol.
258–269. 30 (1), 34–41.
Matsumuro, K., Izumo, S., Higuchi, I., et al., 1993. Acta. Neuro- Sacks, H., Braunstein, V., Brosnan, C., 1987. J. Neuropathol. Exp.
pathol. 86, 547–553. Neurol. 46 (3), 250–261.
Matsusaka, T., Fujii, M., Nakano, T., et al., 1988. Clin. Nephrol. Saiers, J., Slavik, M., Stephens, R., et al., 1987. Cancer Treat. Rep.
30 (6), 341–345. 71 (2), 207–208.
McMaster, M., Greco, F., Johnson, D., et al., 1990. Invest. New Drugs Samavati, A., Othaman, Z., Ghoshal, S.K., et al., 2012. Int. J. Mol. Sci.
8, 87–92. 13 (10), 12880–12889.
Minjajlo, Y.U., Zadorskij, G., Gordienko, N.S., et al., 1978. Izv. Vyss. Sanai, T., Okuda, S., Onoyama, K., et al., 1990a. Nephron 54, 53–60.
Uchebn. Zaved. Chern. Metall 6, 83–86 (in Russian). Sanai, T., Oochi, N., Okuda, S., et al., 1990b. Toxicol. Appl. Pharma-
Mizushima, Y., Shogi, Y., Kaneko, K., 1980. Int. Arch. Allergy Appl. col. 103, 345–353.
Immunol. 63, 338–339. Sanai, T., Okuda, S., Onoyama, K., et al., 1991. Kidney Int. 40,
Mogilevskaja, O. Ja, 1973. In: Israel’son, Z.I., Mogilevskaja, 882–890.
O. Ja, Suvorov, S.Y. (Eds.), Problems of Industrial Hygiene and Scansetti, G., 1992. Sci. Total Environ. 120, 85–91.
­Occupational Pathology in Work with Rare Metals. pp. 227–239. Schauss, A., 1991a. Ren. Failure 13 (1), 1–4.
­Medicina, Moscow (in Russian). Schauss, A., 1991b. Biol. Trace Element Res. 29, 267–280.
Morita, H., Shimomura, S., Okagawa, K., et al., 1986. Sci. Total Schein, P.S., Slavik, M., Smythe, T., et al., 1980. Cancer Treat. Rep. 64,
­Environ. 58, 237–242. 1051–1056.
Nagata, N., Yoneyama, T., Yanagida, K., et al., 1985. J. Toxicol. Sci. Schroeder, H.A., Balassa, J.J., 1967a. J. Chronic. Dis. 20, 211–224.
10, 333–341. Schroeder, H.A., Balassa, J.J., 1967b. J. Nutr. 92, 245–253.
NIST (National Institute of Standards and Technology), 2013. Atomic Schroeder, H.A., Kanisawa, M., Frost, D.V., et al., 1968. J. Nutr. 96,
weights and isotopic compositions for all elements. U.S. ­National 37–45.
Institute of Standards and Technology, G ­aithersburg, MD. Schulman, P., Davis, R., Rafla, S., 1984. Cancer Treat. Res. 68,
Available at http://physics.nist.gov/cgi-bin/Compositions/ 1305–1306.
stand_alone.pl. Seotsanyana-Mokhosi, I., Kresfelder, T., Abrahamse, H., et al., 2006.
NTP (National Toxicology Program), 2011. 12th Report on Car- J. Photochem. Photobiol. B. 83 (1), 55–62.
cinogens.” National Toxicology Program, National Institute of Shamberger, R.J., 2003. Biol. Trace Elem. Res. 94 (2), 123–129.
­Environmental Health Sciences, U.S. Department of Health and Shiga, T., Morimoto, Y., Kubo, N., et al., 2009. J. Nucl. Med. 50 (1),
­Human Services. Available at http://ntp.niehs.nih.gov/?objectid= 148–155.
03C9AF75-E1BF-FF40-DBA9EC0928DF8B15 (accessed 09.03.14). Shinogi, M., Masaki, T., Mori, I., 1989. J. Trace Elem. Electrolytes
Obara, K., Saito, T., Sato, H., et al., 1991. Jpn. J. Med. 30 (1), 67–72. Health Dis. 3, 25–28.
Ochi, A., Ishimura, E., Tsujimoto, Y., et al., 2011. Biol. Trace Elem. Shinohara, A., Chiba, M., Inaba, Y., 1999. J. Anal. Toxicol. 23, 625–631.
Res. 143 (2), 825–834. Slawson, R.M., Van Dyke, M.I., Lee, H., et al., 1992. Plasmid 27 (1),
Ohara, S., 1977. Jpn. Kokai Patent No. 77151713. 72–79.
Ohnishi, A., Yamamoto, T., Murai, Y., et al., 1989. J. UOEH. 11 (3), Snyder, W.S., Cook, M.J., Narset, E.S., et al., 1975. Report of the Task
323–326. Group on Reference Man. p. 385. International Commission
Ohri, L., Vicari, S., Malone, P., 1993. J. Pharm. Technol. 9, 237–241. on Radiological Protection No. 23. Pergamon Press, Oxford-
Okada, K., Okagawa, K., Kawakami, K., et al., 1989. Clin. Nephrol. New York-Toronto-Sydney-Braunschweig.
31, 219–224. Staufer, M., 1980. Erfahrungsheilkunde 29, 646–647 (in German).
Omata, M., Kikuchi, M., Highuchi, C., et al., 1986. In: Tanabe, T., Suzuki, F., Brutkiewicz, R., Pollard, R., 1986. Anticancer. Res. 6,
Hook, J.B., Endo, H. (Eds.), Nephrotoxicin of Antibiotics and Im- 177–182.
munosuppressants. Elsevier Science Publishers B.V., Amsterdam. Swennen, B., Mallants, A., Roels, H., et al., 2000. Occup. Environ.
Osman, M.M., Cohade, C., Nakamoto, Y., et al., 2003. J. Nucl. Med. Med. 57, 242–248.
44 (2), 240–243. Takeuchi, A., Yoshizawa, N., Oshima, S., et al., 1992. Nephron 60 (4),
Ozeki, K., Fukui, Y., Aoki, H., 2006. Biomed. Mater. Eng. 16 (1), 33–41. 436–442.
Pagou, M., Zerizer, I., Al-Nahhas, A., 2009. Hell J. Nucl. Med. 12 (2), Tao, S.-H., Bolger, P.M., 1997. Regul. Toxicol. Pharmacol. 25, 211–219.
102–105. Tomizawa, S., Suguro, N., Kagoshima, H., 1978. Oyo Yakuri 16 (4),
Paone, J., 1970. US. Bur. Mines Bull. 650, 563–571. 671–682 (in Japanese).
Park, M.-K., Han, D.-S., 1979. Soul. Taehakkyo. Yahhak. Nonmunjip. UAz, 2013. Tetradecanoylphorbol acetate. University of Arizona
4, 100–108. Medical Center. http://www.uahealth.com/library/sections/ar
Paul, M., Mason, R., Edwards, R., 1989. Res. Commun. Chem. Pathol. ticle/tetradecanoylphorbol-acetate (accessed 20.12.13).
Pharmacol. 66 (30), 441–450. Underwood, E.J., 1977. Trace Elements in Human and Animal Nutri-
Pei, L.Z., Cai, Z.Y., 2012. Recent Pat. Nanotechnol. 6 (1), 44–59. tion, fourth ed. Academic Press, New York.
Qin, D.W., Gu, Z., Dai, L., et al., 2013. Biol. Trace Elem. Res. 153, USGS (U.S. Geological Survey), 2005. Germanium. U.S. Department
350–354. of the Interior, U.S. Geological Survey. Available at http://mine
Reimann, C., Hall, G., Siewers, U., et al., 1996. Sci. Total Environ. rals.usgs.gov/minerals/pubs/-commodity/germanium/germa
192, 1–19. mcs05.pdf (accessed 13.05.05).
Rochow, E.G., Sindler, B., 1950. J. Am. Chem. Soc. 72, 1218–1220. USGS, 2013. Germanium. U.S. Department of the Interior, U.S.
Roels, H.A., Buchet, J.P., 2001. J. Env. Mon. 3, 67–73. ­Geological Survey. http://minerals.usgs.gov/minerals/pubs/
Rose, M., Baxter, M., Brereton, N., et al., 2010. Food Addit. Contam. commodity/germanium/mcs-2013-germa.pdf. January 2013.
Part A Chem. Anal. Control Expo. Risk Assess. 27 (10), 1380–1404. Velikyan, I., Antoni, G., Sorensen, J., et al., 2013. Am. J. Nucl. Med.
Rosenfeld, G., 1954. Arch. Biochem. Biophys. 48, 84–94. Mol. Imaging 3 (2), 154–165.
Rosenfeld, G., Wallace, E.J., 1953. AMA Arch. Ind. Hyg. Occup. Med. Volgelzang, N.J., Gesme, D.H., Kennedy, B.J., 1985. Am. J. Clin.
8, 466–479. ­Oncol. 8 (4), 341–344.
816 Larry S. Keith, Obaid M. Faroon, Nikki Maples-Reynolds, and Bruce A. Fowler

Wu, C.M., Matsuoka, T., Takemitsu, M., et al., 1992. Muscle Nerve Yesiller, S.U., Yalcin, S., 2013. Anal. Chim. Acta. 770, 7–17.
15, 1258–1264. Yim, S.Y., Lee, I.T., Kim, T.S., 1999. Yonsei. Med. J. 40, 69–75.
Xie, W., Chen, X., Yang, K., 1996. Zhonghua. Yu. Fang. Yi. Xue. Za. Yokoi, K., Kawaai, T., Konomi, A., et al., 2008. Regul. Toxicol. Phar-
Zhi. 30 (2), 88–90. macol. 52 (2), 169–173.
Yamamoto, S., Watabe, H., Kanai, Y., et al., 2012. Radiol. Phys. Yoshinari, O., Shiojima, Y., Igarashi, K., 2013. Br. J. Nutr. Online epub.
­Technol. 5 (1), 59–62. 2013-06-16, 1-6.
Yamanoi, Y., Sendo, J., Kobayashi, T., et al., 2012. J. Am. Chem. Soc. Yuan, F.W., Yang, H.J., Tuan, H.Y., 2012. ACS Nano. 6 (11), 9932–9942.
134 (50), 20433–20439. Zhang, J., Tao, X., Li, C.L., et al., 2011. Zhonghua Lao Dong Wei
Yamasoba, T., Goto, Y., Komaki, H., et al., 2006. Neurosci. Lett. Sheng Zhi Ye Bing Za Zhi 29 (6), 450–451.
395 (1), 18–22. Zhang, M., Zhang, M., 2007. J. Environ. Manage. 85 (2), 393–403.
Yamasoba, T., Someya, S., Yamada, C., et al., 2007. Hear. Res. 226, Zhong, H., Li, Z., Deledalle, F., et al., 2013. J. Am. Chem. Soc. 135 (6),
185–193. 2040–2043.